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Patent Analysis of

Fibrosis susceptibility IL22RA2 gene and uses thereof

Updated Time 12 June 2019

Patent Registration Data

Publication Number

US10150989

Application Number

US14/236869

Application Date

03 August 2012

Publication Date

11 December 2018

Current Assignee

UNIVERSITE D'AIX MARSEILLE,INSERM

Original Assignee (Applicant)

DESSEIN, ALAIN,SERTORIO, MATHIEU,ARGIRO, LAURENT

International Classification

C12Q1/68,C12Q1/6883,C12Q1/6827,C12Q1/683

Cooperative Classification

C12Q1/683,C12Q1/6827,C12Q1/6883,C12Q2600/156,C12Q2539/10

Inventor

DESSEIN, ALAIN,SERTORIO, MATHIEU,ARGIRO, LAURENT

Patent Images

This patent contains figures and images illustrating the invention and its embodiment.

US10150989 Fibrosis susceptibility IL22RA2 gene 1 US10150989 Fibrosis susceptibility IL22RA2 gene 2 US10150989 Fibrosis susceptibility IL22RA2 gene 3
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Abstract

The present invention discloses the identification of a fibrosis susceptibility gene locus, the IL22RA2 gene locus, which can be used for detecting predisposition to, diagnosis and prognosis of fibrosis as well as for the screening of therapeutically active drugs. The invention further provides a method for determining the likelihood of a patient affected with a viral infection to respond to a treatment with an antiviral agent and/or an interferon, which method comprises determining alteration in IL22RA2 gene locus or in IL22RA2 expression or IL22RA2 protein activity in a biological sample of the patient.

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Claims

1. A non-invasive method of preventing or reducing the progression of fibrosis, comprising:

a) obtaining a biological sample from a human subject, wherein the human subject has been infected with a hepatic virus or a parasite; b) detecting at least one single nucleotide polymorphism in a IL22RA2 gene locus of the biological sample, wherein the single nucleotide polymorphism is rs2064501 having a genotype of TT; and c) treating the human subject with an anti-fibrotic therapy.

2. The method of claim 1, wherein the human subject self-identifies as being Chinese, Brazilian, or Sudanese.

3. The method according to claim 1, wherein the hepatic virus is hepatic C virus.

4. The method of claim 1, wherein the sample comprises saliva or blood.

5. The method of claim 1, wherein detecting comprises performing at least one of selective hydridization and sequencing of at least a portion of the IL22RA2 gene locus containing at least one of the single nucleotide polymorphisms.

6. The method of claim 1, wherein the parasite is a Schistosoma parasite.

7. The method of claim 1, comprising detecting at least one additional single nucleotide polymorphism in the IL22RA2 gene locus of the biological sample, wherein the at least one additional single nucleotide polymorphism is rs7774663 having a genotype of CC.

8. The method of claim 1, comprising detecting at least one additional single nucleotide polymorphism in the IL22RA2 gene locus of the biological sample, wherein the at least one additional single nucleotide polymorphism is rs7774663 having a genotype of TT.

9. The method of claim 1, comprising detecting at least one additional single nucleotide polymorphism in the IL22RA2 gene locus of the biological sample, wherein the at least one additional single nucleotide polymorphism is rs6570136 having a genotype of GG.

10. The method of claim 1, comprising detecting at least two additional single nucleotide polymorphisms in the IL22RA2 gene locus of the biological sample, wherein the two additional single nucleotide polymorphisms are rs7774663 having a genotype of CC or TT, and rs6570136 having a genotype of GG.

11. The method of claim 1, wherein detecting comprises performing microsequencing of at least a portion of the IL22RA2 gene locus containing at least one of the single nucleotide polymorphisms.

12. The method of claim 1, wherein detecting comprises performing allele-specific amplification of at least a portion of the IL22RA2 gene locus containing at least one of the single nucleotide polymorphisms.

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Claim Tree

  • 1
    1. A non-invasive method of preventing or reducing the progression of fibrosis, comprising:
    • a) obtaining a biological sample from a human subject, wherein the human subject has been infected with a hepatic virus or a parasite;
    • b) detecting at least one single nucleotide polymorphism in a IL22RA2 gene locus of the biological sample, wherein the single nucleotide polymorphism is rs2064501 having a genotype of TT; and
    • c) treating the human subject with an anti-fibrotic therapy.
    • 2. The method of claim 1, wherein
      • the human subject self-identifies as being Chinese, Brazilian, or Sudanese.
    • 3. The method according to claim 1, wherein
      • the hepatic virus is hepatic C virus.
    • 4. The method of claim 1, wherein
      • the sample comprises
    • 5. The method of claim 1, wherein
      • detecting comprises
    • 6. The method of claim 1, wherein
      • the parasite is a Schistosoma parasite.
    • 7. The method of claim 1, comprising
      • detecting at least one additional single nucleotide polymorphism in the IL22RA2 gene locus of the biological sample, wherein the at least one additional single nucleotide polymorphism is rs7774663 having a genotype of CC.
    • 8. The method of claim 1, comprising
      • detecting at least one additional single nucleotide polymorphism in the IL22RA2 gene locus of the biological sample, wherein the at least one additional single nucleotide polymorphism is rs7774663 having a genotype of TT.
    • 9. The method of claim 1, comprising
      • detecting at least one additional single nucleotide polymorphism in the IL22RA2 gene locus of the biological sample, wherein the at least one additional single nucleotide polymorphism is rs6570136 having a genotype of GG.
    • 10. The method of claim 1, comprising
      • detecting at least two additional single nucleotide polymorphisms in the IL22RA2 gene locus of the biological sample, wherein the two additional single nucleotide polymorphisms are rs7774663 having a genotype of CC or TT, and rs6570136 having a genotype of GG.
    • 11. The method of claim 1, wherein
      • detecting comprises
    • 12. The method of claim 1, wherein
      • detecting comprises
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Description

FIELD OF THE INVENTION

The present invention relates generally to the fields of genetics and medicine. The present invention discloses in particular the identification of a human susceptibility gene, which can be used for the diagnosis or prognosis of an abnormal deposit of Extra Cellular Matrix Proteins (ECMP) in tissue, potentially resulting in fibrosis, or for the detection of predisposition to such abnormal ECMP deposit or fibrosis, occurring in liver diseases, in cirrhosis, cutaneous keloid, obesity and any fibrotic disease and also in disease of other tissues such as heart, vessels or brain. The invention more particularly discloses certain alleles of the IL22RA2 gene on chromosome 6 related to susceptibility to fibrosis and representing novel targets for the screening of therapeutically active drugs. The present invention relates more specifically to particular mutations in the IL22RA2 gene and expression products, as well as to diagnostic tools and kits based on these mutations.

BACKGROUND OF THE INVENTION

Accumulation of Extra Cellular Matrix Proteins in tissue may have deleterious effects. Abnormal deposit of ECMP in tissue may result in tissue fibrosis.

Fibrosis is an excessive growth of fibrous connective tissue in an organ, any part, or tissue thereof, for example in a liver, any part or tissue thereof, especially in response to an injury.

Abnormal fibrosis occurs in chronic hepatic inflammations of various aetiologies such as in Hepatitis Virus and Schistosome infections. It was shown previously that certain subjects infected by Schistosomes are slow fibrosers whereas others are rapid fibrosers and that this depends in part on a major gene located on Chr 6q22-q23 (Dessein et al., 1999; Mohamed-Ali et al., 1999). International patent application WO2010/094740 identifies CTGF (CCN2) as a fibrosis susceptibility gene in this region.

Schistosomiasis is caused by helminths that develop in the vascular system of their hosts and lay eggs that are for some of them carried over to the liver where they trigger inflammation in the periportal space. Since worms live for years in their human host, chronic liver inflammation associated with much tissue destruction is common in infected subjects. Tissue repair requires the deposit of ECMP in the damaged tissues that are later on turned over and replaced by normal hepatocytes. In some patients ECMP accumulate in the periportal space forming fibrosis deposits that reduce blood flow causing varicose veins, ascites. After months or years of chronic or repeated injury, fibrosis becomes permanent and irreversible. Subjects die of the consequences of fibrosis.

In South countries, it is estimated that 5 to 10% of the 350 millions of infected subjects may develop severe hepatic fibrosis. There is no good marker allowing to predict and follow hepatic fibrosis progression in Schistosome infected subjects.

Diagnosis of hepatic fibrosis is mostly based on liver biopsy, elastometry and ultrasound analysis.

Biopsies are obtained via percutanous, transjugular, radiographically-guided fine-needle or laparoscopic route, depending upon the clinical setting. Histopathological examination enables the clinician to grade the severity of necroinflammation and stage the extent of fibrosis. The Metavir scoring system attributes a score to the stages of fibrosis on a 1-4 scale as follows: F0=no fibrosis, F1=portal fibrosis without septa, F2=portal fibrosis and few septae, F3=numerous septae without cirrhosis, F4=cirrhosis (Bedossa et al., 1996). Liver biopsy is an invasive and costly procedure, and samples only a small portion of the liver. Thus it cannot afford a global assessment of hepatic fibrosis, and is subject to sampling variation and inter- and intra-observer error. In addition, liver biopsy is associated with significant morbidity of 3% and a mortality rate of 0.03%. Potential complications include local hematoma, infection and pain related to the biopsy.

Noninvasive tests (i.e., serologic markers, elastometry, ultrasound analysis) are also used but are not yet ready for routine clinical use.

Panels of blood markers have been tested mostly in patients with chronic hepatitis C or cirrhosis due to viral hepatitis C. These studies revealed that serum markers can rule on or rule out fibrosis in approximately 35% of patients (Sebastiani et al., 2006). However, when looking at patients individually, these markers could not reliably differentiate between the various stages of fibrosis. A more recent study incorporated three panels of serum markers to devise an algorithmic approach that improved diagnostic accuracy (Parkes et al., 2006). The three panels evaluated were the APRI (aspartate transaminase to platelet ratio index), the Forns' index (platelets, gammaglutamyltranspeptidase, cholesterol) and the Fibrotest (GGT, haptoglobin, bilirubin, apolipoprotein A, alpha-2-macroglobulin). An algorithm consisting of the APRI followed by the Fibrotest boosted the diagnostic accuracy of fibrosis to above 90%. This group estimated that use of this algorithm could obviate the need for up to 50% of liver biopsies. However, the individual stages of fibrosis are not distinguishable using this algorithm. The limitation of these serum markers is the possibility of false positives when there is highly active hepatic inflammation.

Fibroscan is another approach to staging hepatic fibrosis, which is based on elastography, which provides rapid measurement of mean hepatic tissue stiffness (Ziol et al., 2005). A probe is employed to transmit a vibration of low frequency and amplitude into the liver. This vibration wave triggers an elastic shear wave, whose velocity through the liver is directly proportional to tissuestiffness measured in kilopascals (kPa). Sensitivity of the Fibroscan technique ranged from 79 to 95%, and specificity from 78 to 95%, compared to the liver biopsy. However, the limitations of this technique are associated with attenuation of elastic waves in fluid or adipose tissue, which would impair assessment of fibrosis in patients. In addition, Fibroscan is an extremely expensive instrument.

Today's standard-of-care (SOC) for eradication of HCV from the liver consists of Pegylated type I interferon (PegIFN) and synthetic nucleoside ribavirin (RBV) therapy (Fried M W et al; N Engl J. Med. 2002; 347(13):975-82; EASL Clinical Practice Guideline: Management of hepatitis C virus infection, J. Hepatol. 2011; 55:245-264). However, this standard therapy has limited and unpredictable efficacy, an extensive toxicity profile frequently leading to treatment discontinuation and is very expensive. Less than half of the chronically HCV-infected individuals of genotype 1 and 4 respond to long-term treatment (48 weeks) of standard therapy (PegIFN/RBV) (Testino G et al; Hepatogastroenterology 2011; 58(106):536-8).

Thus, there is a need for a method for selecting patients who have better chances to respond to a treatment in order to optimize treatment, avoid side effects for non-responders and reduce treatment costs.

Altogether there is still a need for an efficient method to prognose the fibrosis progression and the treatment efficiency.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a new genetic approach for fibrosis prognosis and treatment. The present invention now discloses the identification of another human fibrosis susceptibility gene locus, the IL22RA2 gene locus, which can be used for detecting predisposition to, diagnosis and prognosis of an abnormal ECMP deposit, especially fibrosis, especially hepatic fibrosis, as well as for the screening of therapeutically active drugs. The invention resides, in particular, in a method which comprises detecting in a sample from the subject the presence of an alteration in the IL22RA2 gene locus, the presence of said alteration being indicative of the presence or predisposition to an abnormal ECMP deposit or fibrosis.

A particular object of this invention resides in an in vitro method of detecting predisposition to or diagnosis and/or prognosis of an abnormal ECMP deposit or fibrosis occurring in a subject, the method comprising detecting the presence of an alteration in the IL22RA2 gene or polypeptide in a sample from the subject, the presence of said alteration being indicative of the presence of an abnormal ECMP deposit or a fibrosis or the predisposition to an abnormal ECMP deposit or fibrosis. A particular object of this invention resides in a method for assessment (prediction) of the progression of an abnormal ECMP deposit or fibrosis.

In a preferred embodiment, said alteration is located within 500 kb, preferably 100 kb, preferably 20 kb, upstream the start codon of the IL22RA2 gene and within 500 kb, preferably 100 kb, preferably 20 kb, downstream the 3′UTR of the IL22RA2 gene. Preferably, the alteration lies in the surrounding sequences of 10 kb region, upstream the starting codon of the IL22RA2 gene and 10 kb region, downstream the untranslated region (3′UTR).

In another preferred embodiment, said alteration is a mutation, an insertion or a deletion of one or more bases. In a more preferred embodiment, said alteration is one or several single nucleotide polymorphism(s) SNP(s) or a haplotype of SNPs associated with fibrosis. Preferably, said single nucleotide polymorphisms are SNPs flanking IL22RA2 gene, which are allelic variants lying close to the IL22RA2 gene.

The method of the invention allows for detection and prognosis of fibrosis which occurs in a human fibrotic disease selected from hepatic diseases fibrosis, cirrhosis, cutaneous keloid, hypertrophic scars and obesity, alcoholism, or drug hepato-toxicity. Especially, the hepatic fibrosis may be caused by hepatic A virus, hepatic B virus, hepatic C virus (HCV), Schistosoma japonicum (S. japonicum) or Schistosoma mansoni (S. mansoni) infection.

In a particular embodiment, the method comprises genotyping SNPs in the IL22RA2 gene locus in a biological sample of a subject, preferably infected with a hepatitis virus or parasite, wherein the presence of genotype GG in SNP rs6570136, TT in SNP rs7774663, TT, CT in SNP rs11154915 and/or CC in SNP rs2064501, is indicative of a risk of developing an abnormal ECMP deposit such as a fibrosis or of the development of an abnormal ECMP deposit such as a fibrosis, or of a poor prognostic of fibrosis in the subject. The fibrosis is more particularly hepatic fibrosis.

Alternatively the method may comprise genotyping any SNP in Linkage Disequilibrium (LD) with those mentioned herein.

Preferably, the alteration in the IL22RA2 gene locus is determined by performing a selective hydridization assay, a sequencing assay, a microsequencing assay, and/or an allele-specific amplification assay.

In another aspect of the invention, said alteration in the IL22RA2 gene is determined by restriction enzyme digestion, the detection of at least one said SNP being an indication of fibrosis.

This invention also relates to a method for selecting a therapeutic compound for a subject that has or is predisposed to develop an abnormal ECMP deposit such as fibrosis, said method comprising contacting a test compound with a IL22RA2 polypeptide or gene or a fragment thereof and determining the ability of said test compound to enhance or reduce biological activity or function of a pathway related to the IL22RA2 gene.

A further subject of the invention is an in vitro method for determining the likelyhood for a patient affected with a viral infection to respond to a treatment with an antiviral agent and/or an interferon, which method comprises determining alteration in IL22RA2 gene locus or in IL22RA2 protein expression or activity in a biological sample of the patient.

In a particular embodiment, the method comprises comprising genotyping SNPs in the IL22RA2 gene locus in a biological sample of a subject, wherein the presence of a TT genotype with respect to SNP rs11154915, a AG or GG genotype with respect to SNP rs6570136, a CT genotype with respect to SNP rs2064501, and/or a AA genotype with respect to SNP rs1543509, is in favor of a patient's positive response to the treatment. Alternatively the method may comprise genotyping any SNP in Linkage Disequilibrium (LD) with those mentioned herein.

In a particular embodiment, the treatment comprises an antiviral agent, optionally with an interferon.

Preferably said antiviral agent is an inhibitor of viral replication, such as ribavirin.

LEGEND TO THE FIGURES

FIGS. 1A and 1B show IL-22 and IL-17 levels in cultures of PBMC from S. japonicum endemic subjects Data are obtained in 144 hrs resting and egg-stimulated cultures from 19 controls and 70 endemic subjects FIG. 1C shows FACS analysis of IL22+ cells from the blood of endemic subjects. Data are from one representative experiment out of 20.

FIG. 2A shows IL-22 levels in PBMC cultures vary with the number of anti-schistosome treatments over the past ten years. Study subjects were more than 30 and less than 65 years old and had no active HBV infections (HBS Ag-)

Antischistosome treatment: subjects have taken Praziquantel over the past ten years after the following regimens: never, 1 to 4 times, 5-10 times, >10 times.

Controls are subjects who had not been exposed to S. japonicum and never treated with Praziquantel. Stars: Cultures stimulated with S. japonicum eggs; Open circles: Resting cultures: Number of subjects per groups: controls (19), Treatments: no Treatments (9), 1-4 (30), 5-10 (23), <10 (8)

FIG. 2B shows that IL-22 levels in PBMC cultures vary with the degree of hepatic fibrosis.

Study subjects were more than 30 and less than 65 years old and had no active HBV infections (HBS Ag-) Controls are subjects who had not been exposed to S. japonicum; Stars Cultures stimulated with S. japonicum eggs; Open circles: Resting cultures. Fibrosis grade was evaluated as described in Methods and are mostly Central Fibrosis grades, peripheral fibrosis was taken only taken into account to split subjects with mild Central fibrosis into one group (CLL) with no or mild peripheral Fibrosis and one group (CLL, GNM) with mild central fibrosis and advanced to severe (GNM, GNH) peripheral fibrosis. Number of subjects per groups: controls (19), CLL (23), CLL GNM (27), CLM (10), CLH (7), D,E,F (3)

FIG. 2C shows IL-22 levels in subjects with different hepatic fibrosis grades and different treatment. Study subjects were more than 30 and less than 65 years old and had no active HBV infections (HBS Ag-). Controls are subjects who had not been exposed to S. japonicum. Subjects have been treated either 0 to 4 times (open circles) or more than 5 to 20 times (closed circles). Number of subjects per groups: Treatments groups were pooled as follows: 0 to 4 treatments and >5 treatments in order to increase the number of subjects per point

Controls: 19; 0-4 Treatments: 39; >5 Treatments: controls: 31

FIG. 3A shows the impact of the anti-schistosome treatments on IL-22, IL-6, IL-1β, or IL-23 levels in egg-stimulated cultures. Study subjects were more than 30 and less than 65 years old and had no active HBV infections (HBS Ag-) Controls are subjects who had not been exposed to S. japonicum. PBMC from study subjects were stimulated with eggs and cytokines were evaluated in supernatants at 24 hrs (IL-1b, IL-23, IL-6) and at 144 hrs (Il-22). IL-6 levels were multiplied by 0.1.

FIG. 3B shows the IL-22, IL-6, IL-1β or IL-23 levels in egg-stimulated PBMC from controls and from subjects with various degree of Hepatic fibrosis. Study and Number of subjects in each group as for FIG. 2A.

FIG. 3C shows the variations of IL-6, IL-1β, and IL-23 with hepatic fibrosis.

FIG. 4 is a map that locates SNPs and correlation bins in IL22RA2

DETAILED DESCRIPTION OF THE INVENTION

This invention provides valuable genetic markers to predict disease progression in fibrosis, especially in hepatic fibrosis, in humans.

Early detection of an abnormal accumulation of ECMP or fibrosis, and regular monitoring of such accumulation or fibrosis, would allow for initiation of anti-fibrotic therapies capable of halting and even reversing this process. This would in turn prevent progression to human fibrosis disease, for example hepatic fibrosis or hepatic cirrhosis, and the morbidity and mortality this condition entails. The development of these various early fibrosis detection techniques bodes well for the future care of patients with liver disease.

The inventors have now identified a gene associated with human fibrosis. They have shown that fibrosis in Chinese, Sudanese and Brazilian cohorts infected with Schistosoma japonicum and with Schistosoma mansoni respectively is markedly dependent on allelic variants lying in the IL22RA2 gene. The IL22RA2 (for “interleukin-22 receptor alpha-2”) gene, also named IL22R-BP, encodes a soluble form of the IL-22 receptor that competes for the binding of IL-22 to its receptor.

More particularly the inventors performed case control studies on independent samples of Chinese (exposed to S. japonicum), Sudanese and Brazilians (exposed to S. mansoni) all living in endemic regions. Hepatic fibrosis (HF) was evaluated using echography by at least two observers for each sample. All Tag SNPs in IL22RA2 (Minor Allele Frequency>10%) were tested. To rule out whether SNPs in linkage disequilibrium with the associated SNPs could account for the observed associations, the inventors evaluated SNPs in the 500 Kb regions in 3′ and 5′ of IL22RA2.

The invention thus provides a method of determining a risk of developing a hepatic fibrosis or of the development of a hepatic fibrosis, or of a poor prognostic of hepatic fibrosis in a subject, the method comprising detecting the presence of risk-associated single nucleotide polymorphism (SNP) alleles at the IL22RA2 gene locus in a sample from said subject.

The invention more particularly provides a method of determining a risk of developing a hepatic fibrosis or of the development of a hepatic fibrosis, or of a poor prognostic of hepatic fibrosis, the method comprising genotyping a SNP in the IL22RA2 gene locus in a sample from said subject.

Another purpose of the present invention is to provide a genetic approach for predicting the response to viral infection treatment. The present invention now discloses the identification of an antiviral treatment response gene locus, the IL22RA2 gene locus, which can be used for predicting the response to antiviral treatment of a patient suffering from viral infection, especially HCV. The invention resides, in particular, in a method which comprises detecting in a sample from the subject the presence of an alteration in the IL22RA2 gene locus, the presence of said alteration being indicative of the response to the treatment, i.e. being indicative of a level of risk for the patient not to respond to the treatment

The method of the invention allows for prediction of the response to treatment with an antiviral agent such as ribavirin, and an interferon administered to patient suffering of a viral infection, especially hepatitis C.

This invention provides valuable markers to predict response to antiviral treatment, especially in hepatitis C.

Early identification of responders and non-responders subjects to antiviral treatment, would allow for initiation of an individualized (personalized) treatment based on patients' genotype. This would in turn help physicians to make more informed decision, and avoid needless expenditures and unnecessary side effects. The development of these various early prediction techniques bodes well for the future care of patients with viral infection, especially hepatitis C.

The inventors have now identified a gene associated with response to an antiviral treatment. They have shown that response to the antiviral treatment Ribavirin-IFN in various cohorts infected with HCV is dependent on allelic variants lying in the IL22RA2 gene.

Although the experimental data gathered by the inventors did not allow to confirm association of certain alleles, depending on the tested population, the present invention is not limited to the particular SNPs that were found significantly correlated with fibrosis in all tested populations. Indeed, several reasons could account for the failure in confirming significant correlation in some populations, including an insufficient cohort, the incomplete assessment of confounding variables, a lower frequency of the SNPs in said populations, etc.

Definitions

Within the context of this invention, the term “abnormal deposit of Extra Cellular Matrix Proteins (ECMP)” refers to the extracellular matrix components (including laminin, fibronectin EIIIA, collagen I and IV, procollagen III, elastin, tenascin) that may accumulate in all types of human tissues. Such accumulation may be deleterious, for instance when it occurs in arteries, heart, or brain. When the deposition is massive, the accumulation results in fibrosis of the tissue.

Within the context of this invention, “fibrosis” designates all types of human fibrosis occurring in all the fibrotic human diseases, for example in hepatic diseases, cirrhosis, cutaneous keloid, hypertrophic scars, sclerodermia, obesity and any fibrotic disease.

Within the context of this invention, “hepatic fibrosis” or “HF” designates all types of fibrosis occurring in a liver, tissue thereof or any part of tissue thereof. Hepatic fibrosis occurs especially in response to an injury. Hepatic fibrosis can be the common response to chronic liver injury, ultimately leading to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is either overproduced, degraded deficiently, or both. The trigger is chronic injury, especially if there is an inflammatory component. Various types of chronic liver injury can cause fibrosis, such as chemical fibrosis (CCl4), bacterial (i.e., brucellosis), parasitic (i.e., bilharziosis/schistosomiasis caused by Schistosoma species; or echinococcosis infections) or viral (i.e., hepatitis caused by hepatic A virus (HAV), hepatic B virus (HBC) or hepatic C virus (HCV) infections). Within the context of this invention, “cutaneous keloid” is an excessive growth of scar tissue on the skin. More particularly, keloids and hypertrophic scars (HSc) are dermal fibroproliferative disorders unique to humans that occur following trauma, inflammation, surgery, burns and sometimes spontaneously. These are characterized by excessive deposition of collagen in the dermis and the subcutaneous tissues. Contrary to the fine line scar characteristics of normal wound repair, the exuberant scarring of keloid and HSc results typically in disfigurement, contractures, pruritis and pain. Keloids occur in individuals with a familial disposition among the Blacks, Hispanics and Orientals. Unlike HSc, the keloid scars enlarge and extend beyond the margins of the original wound and rarely regress. These disorders represent aberrations in the fundamental processes of wound healing, which include cell migration and proliferation, inflammation, increased synthesis and secretion of cytokines and extra cellular matrix (ECM) proteins and remodelling of the newly synthesized matrix. Biologically, keloids are fibrotic tissue characterized by a collection of atypical fibroblasts with excessive deposition of extracellular matrix components, especially collagen, fibronectin, elastin, and proteoglycans. Generally, keloids contain relatively acellular centers and thick, abundant collagen bundles that form nodules in the deep dermal portion of the lesion. The release and activation of growth factors during the inflammatory phase of healing are pre-requisites for the scar processes, including angiogenesis, reepithelialization, recruitment and proliferation of fibroblasts and matrix deposition. Then, abnormal production of activity of the regulating cytokine including IL22RA2, could contribute to the development of keloids.

Within the context of this invention, “the IL22RA2 gene locus” designates all sequences or products in a cell or organism, including IL22RA2 coding sequences, IL22RA2 non-coding sequences (e.g., introns), IL22RA2 regulatory sequences controlling transcription and/or translation (e.g., promoter, enhancer, terminator, etc.), all corresponding expression products, such as IL22RA2 RNAs (e.g., mRNAs) and IL22RA2 polypeptides (e.g., a pre-protein and a mature protein); as well as surrounding sequences of 500 kb region, preferably 100 kb, preferably 20 kb region, upstream the starting codon of the IL22RA2 gene and 500 kb region, preferably 100 kb, preferably 20 kb region, downstream the untranslated region (3′UTR). For example, the IL22RA2 locus comprises surrounding sequences comprising the SNPs of Table 1.

Within the context of the present invention, the term “prognosis” includes the detection, monitoring, dosing, comparison, etc., at various stages, including early, pre-symptomatic stages, and late stages, in adults, children and pre-birth. Prognosis typically includes the assessment (prediction) of the progression of fibrosis and the characterization of a subject to define most appropriate treatment (pharmaco-genetics), etc. The present invention provides prognostic methods to determine the speed of the progression of fibrosis or an associated disorder resulting from a mutation or a polymorphism in the IL22RA2 gene locus.

The “sample” may be any biological sample derived from a patient or subject, which contains nucleic acids or polypeptides. Examples of such samples include fluids, tissues, cell samples, organs, biopsies, etc. Most preferred samples are blood, plasma, saliva, urine, seminal fluid, etc. The sample may be collected according to conventional techniques and used directly for diagnosis or stored.

The “patient” may be any mammal, preferably a human being, whatever its age or sex. The patient may be infected with a virus, including a virus which is selected from the group consisting of virus of the family of Arenaviridae (e.g. Lassa virus), Coronaviridae (e.g. Sever Acute Respiratory Syndrome virus), Flaviviridae (e.g. Hepatitis C or B Virus, Dengue virus, West Nil Virus, Yellow Fever Virus, Tick-Borne Encephalitis virus), Filoviridae (e.g. Ebola, Marburg), Herpesviridae (e.g. Herpes Simplex Virus, Cytomegalovirus, Epstein-Barr Virus, Varicella Zoster Virus), Orthomyxoviridae (e.g. Influenza A and B), Paramyxoviridae (e.g. Respiratory Syncytial Virus, Paralnfluenza Virus, PMV, Measles), Poxviridae (e.g. Vaccinia, Variola), Rhabdoviridae (e.g. Vesicular Stomatitis Virus, Viral Hemorrhagic Septicemia Virus, Rabies), Retroviridae (e.g. HIV and other retroviruses), Togaviridae (e.g. Chikungunya, Sindbis, Semliki Forest Virus, Ross River Virus, Eastern Equine Encephalitis Virus). In a particular embodiment, the patient is infected with a Hepatitis C virus, e.g. Hepatitis C virus of genotype 1.

In a method for determining the likelyhood for a patient affected with a viral infection to respond to a treatment with an antiviral agent and/or an interferon, the term “viral infection” designated all types of human viral infection which may be treated with Ribavirin and/or IFN, for examples hepatitis C, hepatitis B, Respiratory Syncytial Virus (RSV) bronchiolitis, adenovirus disease, influenza and any human viral infection treated with Ribavirin and/or IFN.

Within the context of this invention, “responder” refers to the phenotype of a patient who responds to the treatment with an antiviral agent, especially Ribavirin, and/or an IFN, i.e. the viral load is decreased, at least one of his symptoms is alleviated, or the development of the disease is stopped, or slowed down.

Within the context of this invention, “non-responder” refers to the phenotype of a patient who either does not respond to the treatment with an antiviral, especially Ribavirin, and/or an IFN, or who responds but relapses within one or two years. Non response to treatment refers to a viral load that does not substantially decrease and patient symptoms are not alleviated, or the disease progresses. Relapsing patients respond to treatment for a short period but their viral load and symptoms increase again within one or two years of the end of the treatment.

The term “treatment” or “antiviral treatment” refers to administration of an antiviral agent and/or interferons (IFN).

Preferably the interferon is interferon gamma. However other interferons are encompassed, including interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau. In a preferred embodiment, the interferon is PEGylated interferon, such as PEGylated interferon gamma.

The “antiviral agent” may be any compound that interferes with the virus entry into a cell, or its replication, or inhibits the activity of a viral protein. For instance it may be interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor, amantadine, or rimantadine. More generally it may be a viral protease inhibitor.

When the virus is HCV virus, the viral agent may be an inhibitor of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, or HCV NS5A protein.

In a preferred aspect, the interferon is interferon gamma, such as PEGylated interferon gamma. In another preferred aspect, the interferon is interferon alpha, such as PEGylated interferon alpha. In a specific embodiment, the treatment comprises ribavirin and interferon gamma or alpha, preferably PEGylated interferon gamma or alpha.

Alterations

The alteration may be determined at the level of the IL22RA2 DNA, RNA or polypeptide. Optionally, the detection is performed by sequencing all or part of the IL22RA2 gene locus or by selective hybridization or amplification of all or part of the IL22RA2 gene locus. More preferably a IL22RA2 gene locus specific amplification is carried out before the alteration identification step. An alteration in the IL22RA2 gene locus may be any form of mutation(s), deletion(s), rearrangement(s) and/or insertions in the coding and/or non-coding region of the locus, alone or in various combination(s). Mutations more specifically include point mutations. Deletions may encompass any region of two or more residues in a coding or non-coding portion of the gene locus, such as from two residues up to the entire gene or locus. Typical deletions affect smaller regions, such as domains (introns) or repeated sequences or fragments of less than about 50 consecutive base pairs, although larger deletions may occur as well. Insertions may encompass the addition of one or several residues in a coding or non-coding portion of the gene locus. Insertions may typically comprise an addition of between 1 and 50 base pairs in the gene locus. Rearrangement includes inversion of sequences. The IL22RA2 gene locus alteration may result in the creation of stop codons, frameshift mutations, amino acid substitutions, particular RNA splicing or processing, product instability, truncated polypeptide production, etc. The alteration may result in the production of a IL22RA2 polypeptide with altered function, stability, targeting or structure. The alteration may also cause a reduction in protein expression or, alternatively, an increase in said production.

In a preferred embodiment, said alteration is a mutation, an insertion or a deletion of one or more bases. In a particular embodiment of the method according to the present invention, the alteration in the IL22RA2 gene locus is selected from a point mutation, a deletion and an insertion in the IL22RA2 gene or corresponding expression product, more preferably a point mutation and a deletion. The alteration may be determined at the level of the IL22RA2 DNA, RNA or polypeptide.

In a most preferred embodiment, the method comprises genotyping the IL22RA2 gene, to determine the presence of a SNP at any of the position indicated in Table 1A.


TABLE 1A
Fibrosis-associated SNPs in the IL22RA2 gene locus
Taqman
MAF (HapMap)
Bin
SNP
Position
Assay Number
SEQ ID
CEU
YRI
CHB
I
rs9376263
137489626
SEQ ID NO: 1
0.41 (T)
0.13 (C)
0.34 (C)
rs6570136
137494622
C_2523610_10
SEQ ID NO: 2
0.42 (A)
0.25 (G)
0.34 (G)
rs6570137
137498645
SEQ ID NO: 3
0.38 (C)
0.13 (T)
0.37 (T)
rs6570138
137501914
SEQ ID NO: 4
0.41 (T)
0.25 (G)
0.34 (G)
rs6570139
137502056
SEQ ID NO: 5
0.41 (A)
0.12 (G)
0.31 (G)
rs6907167
137503761
SEQ ID NO: 6
0.41 (T)
0.25 (G)
0.33 (G)
rs9402876
137509025
SEQ ID NO: 7
0.41 (C)
0.09 (T)
0.32 (T)
rs9402877
137509075
SEQ ID NO: 8
0.41 (A)
0.13 (T)
0.34 (T)
rs9402878
137509292
SEQ ID NO: 9
0.37 (G)
0.29 (T)
0.33 (T)
rs7774663
137510893
C_30217943_10
SEQ ID NO: 10
0.36 (C)
0.33 (T)
0.38 (T)
II
rs13217897
137471327
SEQ ID NO: 11
0.18 (A)
0.26 (A)
0.44 (A)
rs11154913
137474838
SEQ ID NO: 12
0.17 (G)
0.28 (G)
0.44 (G)
rs12664889
137481612
SEQ ID NO: 13
0.18 (A)
0.30 (A)
0.46 (A)
rs13197049
137491211
SEQ ID NO: 14
0.18 (T)
0.26 (T)
0.44 (T)
rs7749054
137500786
C_32241951_10
SEQ ID NO: 15
0.19 (G)
0.26 (G)
0.43 (G)
III
rs202563
137461492
C_3010272_10
SEQ ID NO: 16
0.49 (G)
0.42 (A)
0.26 (G)
rs156751
137463294
SEQ ID NO: 17
0.49 (T)
0.19 (T)
0.26 (T)
IV
rs85462
137463154
SEQ ID NO: 18
0.21 (G)
0.08 (G)
0.16 (G)
rs276467
137464218
SEQ ID NO: 19
0.20 (A)
0.07 (A)
0.16 (A)
rs276466
137466614
C_3010277_10
SEQ ID NO: 20
0.21 (G)
0.07 (G)
0.14 (G)
rs28366
SEQ ID NO: 21
V
rs7750867
137470186
SEQ ID NO: 22
0.16 (T)
0.09 (T)
0.07 (T)
rs9389475
137478484
SEQ ID NO: 23
0.17 (T)
0.07 (T)
0.06 (T)
rs11154914
137480411
SEQ ID NO: 24
0.17 (G)
0.07 (G)
0.07 (G)
rs11154915
137482982
C_9800072_30
SEQ ID NO: 25
0.16 (T)
0.07 (T)
0.05 (T)
rs1040622
137483258
SEQ ID NO: 26
0.16 (C)
0.08 (C)
0.07 (C)
rs10457018
137484893
SEQ ID NO: 27
0.16 (A)
0.08 (A)
0.07 (A)
rs10457019
137484979
SEQ ID NO: 28
0.17 (A)
0.07 (A)
0.07 (A)
rs13441747
137488608
SEQ ID NO: 29
0.17 (C)
0.09 (C)
0.07 (C)
rs9385786
137497052
SEQ ID NO: 30
0.16 (T)
0.07 (T)
0.06 (T)
rs9402875
137498018
SEQ ID NO: 31
0.18 (C)
0.08 (C)
0.06 (C)
rs9385787
137500399
SEQ ID NO: 32
0.17 (C)
0.08 (C)
0.07 (C)
rs9373180
137503455
SEQ ID NO: 33
0.17 (G)
0.04 (G)
0.07 (G)
rs9385789
137505172
SEQ ID NO: 34
0.17 (A)
0.08 (A)
0.07 (A)
VI
rs202567
137470844
SEQ ID NO: 35
0.48 (G)
0.06 (A)
0.22 (A)
rs7774349
137475858
SEQ ID NO: 36
0.48 (C)
0.06 (T)
0.21 (T)
rs2064501
137477823
C_11693858_10
SEQ ID NO: 37
0.48 (T)
0.06 (C)
0.23 (C)
VII
rs1543509
SEQ ID NO: 38
rs17066102
SEQ ID NO: 39
Hapmap: CEU European cohort, YOR African cohort (Yorubas), CHB Asian cohort (Chinese)

Preferably the method comprises genotyping a SNP selected in the group consisting of rs6570136, rs7774663, rs11154915 and rs2064501.

The presence of a G allele with respect to SNP rs6570136, more particularly of a GG genotype, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

The presence of a T allele with respect to SNP rs7774663, more particularly of a TT genotype, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

The presence of a T allele with respect to SNP rs11154915, more particularly of a TT or CT genotype, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

The presence of a C allele with respect to SNP rs2064501, more particularly of a CC genotype, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

SNPs in the same bins are highly correlated (r2>0.8) and of similar utility in the methods of the invention. SNPs in strong linkage disequilibrium (yielding r2>0.6) are encompassed as well.

Another method of the invention may comprise determining whether the patient comprises a genotype of non-response as defined in Table 1B.

Analysis was performed on 123 subjects (69 responder subjects and 54 non responder subjects), all infected with HCV.


TABLE 1B
Antiviral treatment response-associated alterations in the IL22RA2 gene
locus
SEQ
Responder
% with RG
% with RG
ID
Genotype
in
in Non
Bin
SNP
NO:
(RG)
Responders
Responders
p
OR
CI
Univariate analysis
I
rs7774663
10
CT, TT
89
79.3
0.13
2.1
0.8-5.6
I
rs6570136
2
AG, GG
78.6
66.1
0.12
1.9
0.85-4.2 
II
rs7749054
15
TT
71.6
58.6
0.1
1.8
0.9-3.7
III
rs202563
16
AG, GG
87.7
75.4
0.07
2.3
0.9-5.8
IV
rs28366
21
CC, TC
44.6
32.1
0.15
1.7
0.8-3.5
IV
rs276466
20
0.3
V
rs11154915
25
TT
6.8
1.7
0.2
4.2
0.5-37
VI
rs2064501
37
CT
54.8
32.8
0.013
2.5
1.2-5.1
VII
rs1543509
38
AA
90.5
73.2
0.012
3.5
1.3-9.3
Multivariate analysis
I
rs6570136
2
GG
0.16
1.9
0.8-4.7
V
rs11154915
25
TT
0.03
13.7
 1.3-146
VI
rs2064501
37
CT
0.004
3.6
1.5-8.5
VII
rs1543509
38
AA
0.014
3.9
 1.3-11.5

Preferably the method comprises genotyping a SNP selected in the group consisting of rs11154915, rs6570136, rs2064501 and rs1543509.

The presence of a TT genotype with respect to SNP rs11154915, is in favor of a patient's positive response to the antiviral treatment.

The presence of a AG or GG genotype with respect to SNP rs6570136, is in favor of a patient's positive response to the antiviral treatment.

The presence of a CT genotype with respect to SNP rs2064501, is in favor of a patient's positive response to the antiviral treatment

The presence of a AA genotype with respect to SNP rs1543509, is in favor of a patient's positive response to the antiviral treatment.

SNPs in the same bins are highly correlated (r2>0.8) and of similar utility in the methods of the invention. SNPs in linkage disequilibrium are encompassed as well.

Odd ratios associated with each genotype are indicated in Table 1B. They vary from 1.9 to 4 when each SNP was evaluated alone; when all SNPs were evaluated together in the same multivariate model (that takes into account confounding effects between SNPs) ORs vary from 1.9 to 13, and a subjects who will carry responder genotypes for all four polymorphisms will be around 50 to 300 times more likely to respond to treatment that a subjects carrying non responder genotypes for all genotypes.

Linkage disequilibrium (LD) is defined as the non-random association of alleles at different loci across the genome. Alleles at two or more loci are in LD if their combination occurs more or less frequently than expected by chance in the population.

When there is a causal locus in a DNA region, due to LD, one or more SNPs nearby are likely associated with the trait too. Therefore, any SNPs in strong LD (yielding a r2>0.6) with a first SNP associated with an abnormal ECMP deposit will be associated with this trait.

Identification of additional SNPs in linkage disequilibrium with a given SNP involves: (a) amplifying a fragment from the genomic region comprising or surrounding a first SNP from a plurality of individuals; (b) identifying of second SNPs in the genomic region harboring or surrounding said first SNP; (c) conducting a linkage disequilibrium analysis between said first SNP and second SNPs; and (d) selecting said second SNPs as being in linkage disequilibrium with said first marker. Subcombinations comprising steps (b) and (c) are also contemplated.

Methods to identify SNPs and to conduct linkage disequilibrium analysis can be carried out by the skilled person without undue experimentation by using well-known methods.

It is well known that many SNPs have alleles that show strong LD with other nearby SNP alleles and in regions of the genome with strong LD, a selection of evenly spaced SNPs, or those chosen on the basis of their LD with other SNPs (proxy SNPs or Tag SNPs), can capture most of the genetic information of SNPs, which are not genotyped with only slight loss of statistical power. In association studies, this region of LD are adequately covered using few SNPs (Tag SNPs) and a statistical association between a SNP and the phenotype under study means that the SNP is a causal variant or is in LD with a causal variant. The two metrics most commonly used to measure LD are D′ and r2 and can be written in terms of each other and allele frequencies. It is a general consensus that a proxy (or Tag SNP) is defined as a SNP in LD (r2≥0.8) with one or more other SNPs. The genotype of the proxy SNP could predict the genotype of the other SNP via LD and inversely. In particular, any SNP in LD with one of the SNPs used herein may be replaced by one or more proxy SNPs defined according to their LD as r2≥0.8.

These SNPs in linkage disequilibrium can also be used in the methods according to the present invention, and more particularly in the diagnostic methods according to the present invention.

Alterations in the IL22RA2 gene may be detected by determining the presence of an altered IL22RA2 RNA expression. Altered RNA expression includes the presence of an altered RNA sequence, the presence of an altered RNA splicing or processing, the presence of an altered quantity of RNA, etc. These may be detected by various techniques known in the art, including by sequencing all or part of the IL22RA2 RNA or by selective hybridisation or selective amplification of all or part of said RNA, for instance.

In a further variant, the method comprises detecting the presence of an altered IL22RA2 polypeptide expression. Altered IL22RA2 polypeptide expression includes the presence of an altered polypeptide sequence, the presence of an altered quantity of IL22RA2 polypeptide, the presence of an altered tissue distribution, etc. These may be detected by various techniques known in the art, including by sequencing and/or binding to specific ligands (such as antibodies), for instance.

As indicated above, various techniques known in the art may be used to detect or quantify altered IL22RA2 gene or RNA expression or sequence, including sequencing, hybridisation, amplification and/or binding to specific ligands (such as antibodies). Other suitable methods include allele-specific oligonucleotide (ASO), allele-specific amplification, Southern blot (for DNAs), Northern blot (for RNAs), single-stranded conformation analysis (SSCA), PFGE, fluorescent in situ hybridization (FISH), gel migration, clamped denaturing gel electrophoresis, heteroduplex analysis, RNase protection, chemical mismatch cleavage, ELISA, radio-immunoassays (RIA) and immuno-enzymatic assays (IEMA). Some of these approaches (e.g., SSCA and CGGE) are based on a change in electrophoretic mobility of the nucleic acids, as a result of the presence of an altered sequence. According to these techniques, the altered sequence is visualized by a shift in mobility on gels. The fragments may then be sequenced to confirm the alteration. Some others are based on specific hybridization between nucleic acids from the subject and a probe specific for wild-type or altered IL22RA2 gene or RNA. The probe may be in suspension or immobilized on a substrate. The probe is typically labelled to facilitate detection of hybrids. Some of these approaches are particularly suited for assessing a polypeptide sequence or expression level, such as Northern blot, ELISA and RIA. These latter require the use of a ligand specific for the polypeptide, more preferably of a specific antibody.

In a preferred embodiment, the method comprises detecting the presence of an altered IL22RA2 gene expression profile in a sample from the subject. As indicated above, this can be accomplished more preferably by sequencing, selective hybridisation and/or selective amplification of nucleic acids present in said sample.

Sequencing

Sequencing can be carried out using techniques well known in the art, using automatic sequencers. The sequencing may be performed on the complete IL22RA2 gene locus or, more preferably, on specific domains thereof, typically those known or suspected to carry deleterious mutations or other alterations.

Amplification

Amplification is based on the formation of specific hybrids between complementary nucleic acid sequences that serve to initiate nucleic acid reproduction. Amplification may be performed according to various techniques known in the art, such as by polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA) and nucleic acid sequence based amplification (NASBA). These techniques can be performed using commercially available reagents and protocols. Preferred techniques use allele-specific PCR or PCR-SSCP. Amplification usually requires the use of specific nucleic acid primers, to initiate the reaction. Nucleic acid primers useful for amplifying sequences from the IL22RA2 gene locus are able to specifically hybridize with a portion of the IL22RA2 gene locus that flank a target region of said locus, said target region being altered in certain subjects having fibrosis or associated disorders.

This invention makes use of nucleic acid primers useful for amplifying sequences from the IL22RA2 gene or locus including surrounding regions. Such primers are preferably complementary to, and hybridize specifically to nucleic acid sequences in the IL22RA2 gene locus. Particular primers are able to specifically hybridize with a portion of the IL22RA2 gene locus that flank a target region of said locus, said target region being altered in certain subjects having fibrosis or associated disorders.

Selective Hybridization

Hybridization detection methods are based on the formation of specific hybrids between complementary nucleic acid sequences that serve to detect nucleic acid sequence alteration(s). A particular detection technique involves the use of a nucleic acid probe specific for wild-type or altered IL22RA2 gene or RNA, followed by the detection of the presence of a hybrid. The probe may be in suspension or immobilized on a substrate or support (as in nucleic acid array or chips technologies). The probe is typically labeled to facilitate detection of hybrids. In this regard, a particular embodiment of this invention comprises contacting the sample from the subject with a nucleic acid probe specific for an altered IL22RA2 gene locus, and assessing the formation of a hybrid. In a particular preferred embodiment, the method comprises contacting simultaneously the sample with a set of probes that are specific, respectively, for wild type IL22RA2 gene locus and for various altered forms thereof. In this embodiment, it is possible to detect directly the presence of various forms of alterations in the IL22RA2 gene locus in the sample. Also, various samples from various subjects may be treated in parallel.

Within the context of this invention, a probe refers to a polynucleotide sequence which is complementary to and capable of specific hybridization with a (target portion of a) IL22RA2 gene or RNA, and which is suitable for detecting polynucleotide polymorphisms associated with IL22RA2 alleles which predispose to or are associated with fibrosis. Probes are preferably perfectly complementary to the IL22RA2 gene, RNA, or target portion thereof. Probes typically comprise single-stranded nucleic acids of between 8 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500. It should be understood that longer probes may be used as well. A preferred probe of this invention is a single stranded nucleic acid molecule of between 8 to 500 nucleotides in length, which can specifically hybridize to a region of a IL22RA2 gene locus or RNA that carries an alteration.

The method of the invention employs a nucleic acid probe specific for an altered (e.g., a mutated) IL22RA2 gene or RNA, i.e., a nucleic acid probe that specifically hybridizes to said altered IL22RA2 gene or RNA and essentially does not hybridize to a IL22RA2 gene or RNA lacking said alteration. Specificity indicates that hybridization to the target sequence generates a specific signal which can be distinguished from the signal generated through non-specific hybridization. Perfectly complementary sequences are preferred to design probes according to this invention. It should be understood, however, that certain mismatch may be tolerated, as long as the specific signal may be distinguished from non-specific hybridization. Particular examples of such probes are nucleic acid sequences complementary to a target portion of the genomic region including the IL22RA2 gene locus or RNA carrying a point mutation as listed in Table 1 above.

The sequence of the probes can be derived from the sequences of the IL22RA2 gene and RNA as provided in the present application. Nucleotide substitutions may be performed, as well as chemical modifications of the probe. Such chemical modifications may be accomplished to increase the stability of hybrids (e.g., intercalating groups) or to label the probe. Typical examples of labels include, without limitation, radioactivity, fluorescence, luminescence, enzymatic labelling, etc. The invention also concerns the use of a nucleic acid probe as described above in a method of detecting the presence of or predisposition to fibrosis or an associated disorder in a subject or in a method of assessing the response of a subject to a treatment of fibrosis or an associated disorder.

Specific Ligand Binding

As indicated above, alteration in the IL22RA2 gene locus may also be detected by screening for alteration(s) in IL22RA2 polypeptide sequence or expression levels. In this regard, contacting the sample with a ligand specific for a IL22RA2 polypeptide and determining the formation of a complex is also described. Different types of ligands may be used, such as specific antibodies. In a specific embodiment, the sample is contacted with an antibody specific for a IL22RA2 polypeptide and the formation of an immune complex is determined. Various methods for detecting an immune complex can be used, such as ELISA, radio-immunoassays (RIA) and immuno-enzymatic assays (IEMA). Within the context of this invention, an antibody designates a polyclonal antibody, a monoclonal antibody, as well as fragments or derivatives thereof having substantially the same antigen specificity. Fragments include Fab, Fab′2, CDR regions, etc. Derivatives include single-chain antibodies, humanized antibodies, poly-functional antibodies, etc. An antibody specific for a IL22RA2 polypeptide designates an antibody that selectively binds a IL22RA2 polypeptide, i.e., an antibody raised against a IL22RA2 polypeptide or an epitope-containing fragment thereof. Although non-specific binding towards other antigens may occur, binding to the target IL22RA2 polypeptide occurs with a higher affinity and can be reliably discriminated from non-specific binding.

It is also disclosed a diagnostic kit comprising products and reagents for detecting in a sample from a subject the presence of an alteration in the IL22RA2 gene locus or polypeptide, in the IL22RA2 gene or polypeptide expression, and/or in IL22RA2 activity. Said diagnostic kit comprises any primer, any pair of primers, any nucleic acid probe and/or any ligand, preferably antibody, described in the present invention. Said diagnostic kit can further comprise reagents and/or protocols for performing a hybridization, amplification or antigen-antibody immune reaction.

Drug Screening

New methods for the screening of drug candidates or leads are also described. These methods include binding assays and/or functional assays, and may be performed in vitro, in cell systems, in animals, etc. A particular object of this invention resides in a method of selecting biologically active compounds, said method comprising contacting in vitro a test compound with a IL22RA2 gene or polypeptide according to the present invention and determining the ability of said test compound to bind said IL22RA2 gene or polypeptide. Binding to said gene or polypeptide provides an indication as to the ability of the compound to modulate the activity of said target, and thus to affect a pathway leading to any abnormal deposit of ECMP or fibrosis in a subject. In a preferred embodiment, the method comprises contacting in vitro a test compound with a IL22RA2 polypeptide or a fragment thereof according to the present invention and determining the ability of said test compound to bind said IL22RA2 polypeptide or fragment. The fragment preferably comprises a binding site of the IL22RA2 polypeptide. Preferably, said IL22RA2 gene or polypeptide or a fragment thereof is an altered or mutated IL22RA2 gene or polypeptide or a fragment thereof comprising the alteration or mutation. A particular object of this invention resides in a method of selecting compounds active on any abnormal deposit of ECMP or fibrosis, said method comprising contacting in vitro a test compound with a IL22RA2 polypeptide according to the present invention or binding site-containing fragment thereof and determining the ability of said test compound to bind said IL22RA2 polypeptide or fragment thereof. Preferably, said IL22RA2 polypeptide or a fragment thereof is an altered or mutated IL22RA2 polypeptide or a fragment thereof comprising the alteration or mutation. The method for the screening of drug candidates comprises contacting a recombinant host cell expressing a IL22RA2 polypeptide according to the present invention with a test compound, and determining the ability of said test compound to bind said IL22RA2 and to modulate the activity of IL22RA2 polypeptide. Preferably, said IL22RA2 polypeptide or a fragment thereof is an altered or mutated IL22RA2 polypeptide or a fragment thereof comprising the alteration or mutation. The determination of binding may be performed by various techniques, such as by labelling of the test compound, by competition with a labelled reference ligand, etc. The method of selecting biologically active compounds also comprises contacting in vitro a test compound with a IL22RA2 polypeptide and determining the ability of said test compound to modulate the activity of said IL22RA2 polypeptide. Preferably, said IL22RA2 polypeptide or a fragment thereof is an altered or mutated IL22RA2 polypeptide or a fragment thereof comprising the alteration or mutation. The method of selecting biologically active compounds for a subject that has or is predisposed to develop any abnormal deposit of ECMP or fibrosis, also comprises contacting in vitro a test compound with a IL22RA2 gene according to the present invention and determining the ability of said test compound to modulate the expression of said IL22RA2 gene. Preferably, said IL22RA2 gene or a fragment thereof is an altered or mutated IL22RA2 gene or a fragment thereof comprising the alteration or mutation.

The method of screening, selecting or identifying active compounds, particularly compounds active on any abnormal deposit of ECMP or fibrosis, also comprises contacting a test compound with a recombinant host cell comprising a reporter construct, said reporter construct comprising a reporter gene under the control of a IL22RA2 gene promoter, and selecting the test compounds that modulate (e.g. activate or inhibit) expression of the reporter gene. Preferably, said IL22RA2 gene promoter or a fragment thereof is an altered or mutated IL22RA2 gene promoter or a fragment thereof comprising the alteration or mutation.

The above screening assays may be performed in any suitable device, such as plates, tubes, dishes, flasks, etc. Typically, the assay is performed in multi-wells plates. Several test compounds can be assayed in parallel. Furthermore, the test compound may be of various origin, nature and composition. It may be any organic or inorganic substance, such as a lipid, peptide, polypeptide, nucleic acid, small molecule, etc., in isolated or in mixture with other substances. The compounds may be all or part of a combinatorial library of products, for instance.

Further aspects and advantages of the present invention will be disclosed in the following experimental section, which should be regarded as illustrative and not limiting the scope of the present application.

EXAMPLES

Example 1: Production and Modulation of IL-22 in Human Schistosome Infections Production of IL-22 in Human Schistosome Infections

The inventors have compared IL-22 levels in cultures of PBMC from 140 subjects exposed to S. japonicum infections with cultures of 20 controls who had no previous exposure to schistosome infections (FIG. 1A) but lived in the same region in comparable living conditions. IL-22 was detected in resting cultures of exposed subjects at 72 and 144 hrs and was significantly enhanced by addition of schistosome eggs at time 0 of the culture. IL-22 was detected in control resting cultures at 144 hrs only and was not enhanced by addition of eggs. The inventors detected significant IL-17A levels in 144 hrs cultures but IL-17 levels were not enhanced by egg-stimulation (FIG. 1B). Thus it is unlikely that IL-22 in the cultures was produced by Th17. Analysis by FACS of the IL22+ cells in the blood of exposed patients showed IL-22 is produced by CD3+CD4+ and by CD3−CD4− none of these cells populations produced IL-17 (FIG. 1C). The latter likely are NK cells. The percentage of CD3+CD4+IL17−IL22+ T cells and CD3−CD4−IL17−IL22+ in control and endemic subjects are shown on FIG. 1C.

Modulation of IL-22 production is modified by the anti-schistosome treatment and is modulated accordingly to hepatic fibrosis.

IL-22 levels in egg-stimulated cultures varied markedly among exposed subjects. Since anti-schistosome Praziquantel treatments destroy the worms and shut off egg production until reinfection occurs, we evaluated whether differences in Praziquantel treatments could have modulated IL-22 production. Certain patients had been treated every year for at least 10 years, others had never been treated and others had received 1 to 10 treatments in the past 10 years. FIG. 2A shows the number of Praziquantel treatments had a significant impact on IL-22 production by subjects PBMC: IL-22 in egg-stimulated cultures augmented significantly with the number of treatments over the past ten years (p=0.005, covariate in the regression model was gender p=0.08); this effect was however much less for subjects who had been treated at least once a year every year probably because these subjects were not getting reinfected (see below). Then the frequency of Praziquantel treatments over the last ten years had impacted significantly on IL-22 production by PBMC from exposed subjects.

The inventors then evaluated whether IL-22 levels in cultures were related to the degree of patient's liver disease. FIG. 2B shows that IL-22 was low in subjects with mild liver disease as measured by hepatic fibrosis grades and augmented steadily with increased fibrosis grades reaching maximum levels in subjects with advanced central periportal fibrosis. This suggests that increased production of IL-22 may occur in response to/in association with severe hepatic disease. Strikingly, however, IL-22 from patients with very severe hepatic fibrosis (HF grades D,E,F) failed to produce much IL-22.

The effect of the number of Praziquantel treatments on this pattern is shown on FIG. 2C. Praziquantel treatments impacted IL-22 produced by cells from all fibrosis groups. Three observations are most relevant to our study: first the increase IL-22 production in advanced fibrosis (CLH) is observed at different Praziquantel regimens and is not due to differences in the frequency of treatment of this patients; second, Praziquantel treatments improved IL-22 production in all cultures but in cultures of cells from subjects with severe fibrosis grades; third, subjects with the high Praziquantel regimens (>10, once at least every year) are in the mild fibrosis group and account for the increase of IL-22 production observed in this group. In summary, IL-22 is impacted by two independent factors the Praziquantel treatments and the degree of hepatic disease. Moreover subjects with very severe hepatic disease fail to produce much IL-22 and this was not improved by Praziquantel treatments whereas the same treatments had a marked enhancing effect on IL-22 production by subjects with mild to advanced hepatic fibrosis.

IL-6 and possibly IL-1β likely are key regulators of IL-22 production in subjects with different hepatic fibrosis grades and different treatment regimens.

The inventors observed that cytokines IL-6, IL-1β and IL-23 were significantly enhanced (IL-23 (p=3.10-6), IL-6 (p<10-6) and IL-1β (p<10-6) by egg stimulation in 24 hrs cultures of PBMC from exposed subjects (FIG. 3A). To determine whether any of these 3 cytokine could play a role in modulating IL-22 levels, we performed a linear regression analysis with IL-22 levels in egg-stimulated cultures including these 3 cytokines, patient age and gender. This analysis showed a highly significant (p=0.0002) association between IL-22 and IL-6 and a weak association (p=0.06) with IL-1β. IL-23 was excluded from the regression model. This result is illustrated in FIGS. 3B, 3C that shows the variations of IL-6, IL-1β, and IL-23 with Praziquantel treatments (FIG. 3B) and with hepatic fibrosis (FIG. 3C). Thus, the link between Praziquantel treatments and IL-22 and Fibrosis grades and IL-22 is, at least in part, IL-6.

The results presented above are consistent with the view that the recruitment of a protective IL-22 response increased with hepatic damage and that the most severe hepatic disease may result in part from the inability to recruit such response. To test further this hypothesis the inventors looked for genetic evidence indicating the IL-22 was indeed crucial in the control of hepatic fibrosis and had a significant impact on hepatic disease.

Example 2: Polymorphisms in IL22RA2 Encoding IL22 BP are Associated with Hepatic Fibrosis in Two Samples of Chinese Fishermen and Farmers Living in an Endemic Area of S. japonicum

Materials and Methods

Statistical Analysis

Multivariate logistic regression was used to analyse the relationship between the probability of an individual developing fibrosis and genetic variants including the main covariates known to affect disease progression in subjects infected with schistosomes. The statistical SPSS software (version 10.0) was used for this analysis. Age, gender, and exposure to infection, were tested in the regression models and kept when they showed an association (p<0.05) with disease. Since the cohorts were matched for gender and age, these covariates had little effects on the association between genetic variants and disease. Infection with HBV and exposure to infection were included in the regression models when these covariates could be evaluated accurately as in the Chinese fishermen (exposure, number of treatments) or in the Chinese farmers (HBV infection, place of birth).

DNA Extraction

Aliquots of 5 to 15 ml of blood were collected on sodium citrate and kept at −20° C. DNA was extracted using the standard salting out method (Sambrook et al., 1989).

DNA Amplification

All the DNA purified from FTA card were pre amplified before genotyping. Polymerase chain reactions (whole genome amplifications) were conducted in 50 μl reactions containing one punch of biological sample (FTA1-bound buccal cell DNA) or 100 ng of genomic DNA, 1.5 OD of 15-base totally degenerate random primer (Genetix, Paris, France), 200 mM dNTPs, 5 mM MgCl2, 5 ml of 10×PCR buffer and 0.5 unit of high fidelity Taq DNA polymerase (BIOTAQ DNA Polymerase, Bioline London, England). Samples were amplified in a multiblock thermocycler as follows: a pre-denaturation step of 3 min at 94° C., 50 cycles consisting of 1 min at 94° C., 2 min at 37° C., 1 min of ramp (37-55° C.), and 4 min at 55° C. Final extension step of 5 min at 72° C.

Sequencing

Purified PCR products were sequenced using ABI Prism BigDye Terminator cycle sequencing system (PE Applied Biosystems, Foster City, U.S.A.) on ABI Prism automatic sequencer. Sequencing reactions were performed on both strands Sequencing by GATC biotech (GATC, Marseille France).

Polymorphism Genotyping by PCR with Specific TaqMan Probes

Allelic discrimination was assessed using TaqMan probe assays (Applied Biosystems, Lafayette USA). Each reaction contained 12.5 ng of genomic DNA, TaqMan Universal PCR Master Mix (Applied Biosystems, Lafayette USA), 900 nM of each primer and 200 nM of each fluorescently-labelled hybridisation probe in a total volume of 5 μl. RT-PCR was conducted in an ABI Prism Sequence Detection System 7900 (Applied Biosystems, Lafayette USA) using the following conditions: 50° C. for 2 min, 95° C. for 10 min and 40 cycles of amplification (95° C. denaturation for 15 s, 60° C. annealing/extension for 1 min).

Results

The inventors have selected in HapMap data basis the SNPs comprise in IL22RA2 (29.7 Kb) and 10 Kb in 3′ and 5′ of the gene that had a Minor allele frequency in Chinese greater than 10%. These SNPs were grouped in six correlation (r2=0.8) bins containing n=10 (bin I), 5 (II), 2 (III), 3 (IV), 13 (V) and 3 (VI), and 4 singletons which are positioned as in FIG. 4. The inventors genotyped one or two SNPs from each bins in a sample of Chinese fishermen (n=268, 176 subjects with mild HF and 92 patients with severe HF) who have been fishing for at least 20 years in the Dong Ting lake where S. japonicum has been endemic for at least 40 years. They found that 3 SNPs belonging to two bins were associated with HF. SNP rs6570136 GG (p=0.007, OR=2.7 (CI=1.3-5.6)), rs7774663 TT (p=0.006, OR=2.5 (1.3-4.7)) both in bin I and rs7749054 TT (p=0.045, OR=1.8 (1.1-3.1)) showed some association with HF (Table 2). The significant covariates introduced in the statistical model, were gender (p<10-3, OR=6.9 (2.8-17)), Exposure (Number of fishing years) (p=0.05, OR=1.02 (1-1.05)), splenectomy (p=0.008, OR=6.6 (1.6-27)). Multivariate analysis testing two SNPs simultaneously in the same models in the presence of the same covariates indicated that SNPrs 11154915 TC was associated (p=0.04, OR=1.9 (1-3.5) when tested in the presence of rs 6570136 (p=0.007 OR=2.9 (1.4-6). Interestingly (see study in Sudanese and Brazilians) SNP rs 2064501 showed a trend to association with HF that was not reduced when other SNPs were introduced in the regression model.

Finally, the association of rs7749054 was likely due to its LD with SNPs in bin I since the association of rs7749054 with HF was totally lost in the presence of either SNP rs6570136 or SNP rs7774663.


TABLE 2
SNPs of IL22RA2 associated with Hepatic fibrosis: analysis in Chinese
fishermen
Chinese fisherman sample
Controls
Cases
SNP
Position
Bin
Genotype
%
%
OR
95% CI
p
Univariate
rs6570136
137536315
I
GG
13.0
22.1
2.7
1.3-5.6
0.007
analysis
rs7774663
137552586
I
TT
18.1
28.4
2.5
1.3-4.7
0.006
rs7749054
137542479
II
TT
32.8
41.1
1.8
1.0-2.9
0.045
rs202563
137503185
III
AA
38.7
45.8
0.3
rs276466
137508307
IV
AG + GG
24.3
30.2
>0.5
rs11154915
137524675
V
CT (no TT)
97.2
99.1
0.16
rs2064501
137519516
VI
CC + TT
55.4
62.5
0.17
Multivariate
rs6570136
I
GG
2.9
1.4-6.0
0.007
analysis
rs11154915
V
CT (no TT)
1.9
1.0-3.5
0.04
Model 1
(n = 268, 92 cases and 176 controls)

The inventors then attempted to replicate these results in a second Chinese sample from farmers from a region endemic for S. japonicum. This sample differs from the fisherman sample because it was hospital based recruited from an outpatient clinic caring for severe hepatic disease including ascites, bleeding from varices and cirrhosis. 92.2% of the recruited patients were living in a region where S. japonicum was still endemic, 7.8% had been living in a schistosome endemic region but transmission in their region had been interrupted ten to fifteen years ago. A fraction (86.5%) of these subjects had evidence of previous HBV infection (20.9% AgHBS+) one patient had been infected with HCV. Thus liver disease in most farmers of this second sample likely results from both schistosome and HBV infections.

All SNPs tested in the Fisherman sample were genotyped on the Farmer sample (298, 97 subjects with mild hepatic disease and 201 subjects with severe hepatic disease). Association with hepatic disease was observed with 4 SNPs from 3 different bins: SNP rs6570136 GG,GA (p=0.009, OR=2 (1.2-3.3)), rs7774663 TT,TC (p=0.01, OR=2 (1.2-3.3) both in bin I; SNP rs 276466 GA (p=0.01, OR=2.2 (1.2-4)) in bin IV; SNP rs1114915 CC,CT (p=0.04, OR=5.7 (1.1-29.6)) in bin V (Table 3). Trends for association were also observed for SNP rs202563 AA,GG (p=0.06) in bin III and SNP rs2064501 CT (p=0.08). Covariates in these association test were Age (p=0.05, OR=1.03 (1-1.06), gender (p=0.02, OR=2.3 (1.1-4.8) and whether the patient was living in endemic/non endemic region (p=0.09, OR=2). Multivariate analysis performed on SNPs from different bins indicated two possible statistical models: one model included SNPs rs6570136 (or rs7774663) (p=0.03, OR=1.8 (1.1-3)) in bin I and SNP rs11154915 (p=0.1, OR=4 (0.8-21.2)) in bin V; the other model included SNP rs 276466 (p=0.02, OR=2 (1.1-3.8)) and SNP rs11154915 (p=0.05, OR=9.2 (1.1-80)). The analysis could not discriminate between these two models.


TABLE 3
SNPs of IL22RA2 associated with Hepatic fibrosis; analysis in Chinese
farmers
Chinese farmer sample
Controls
Cases
SNP
Position
Bin
Genotype
%
%
OR
95% CI
p
Univariate analysis
rs6570136
137536315
I
GG + AG
53.6
67.8
2
1.2-3.3
0.009
rs7774663
137552586
I
CT + TT
58.8
72.3
2
1.2-3.3
0.01
rs7749054
137542479
II
GG
15.1
18.9
0.5
rs202563
137503185
III
AA + GG
46.9
57.3
1.6
0.98-2.7 
0.06
rs276466
137508307
IV
AG (no GG)
18.7
34.5
2.2
1.2-4.0
0.01
rs11154915
137524675
V
CC + CT
93.8
99.3
5.7
 1.1-29.6
0.036
rs2064501
137519516
VI
CT
40.2
51.2
1.6
0.95-2.7 
0.08
Multivariate analysis
rs6570136
I
GG + AG
1.6
  1-2.6
0.06
Model 1
rs11154915
V
CT + TT
4.8
0.93-25  
0.06
(n = 298, 201 cases and 97 controls)

Example 3: Extension of the Association to Populations from Sudan and Brazil Exposed to Schistosoma mansoni

To assess whether our observation could be extended to subjects infected with S. mansoni we tested the same SNPs in a sample from Sudan and in a sample from Brazil. Again a significant fraction of subjects in the Sudanese sample as in the Chinese farmer had also been infected with HBV whereas only very few Brazilian had HBV infections.

Genotyping the Sudanese sample (n=202, 144 mild HF and 58 severe HF) showed that SNP rs6570136 GG (p=0.01, OR=3.1 (1.3-7.2)), rs7774663 TT,TC (p=0.01, OR=1.7 (1-3.1), rs11154915 TT (p=0.05, OR=6.2 (1-35.3)) showed associations with HF whereas a trend for association was also detected for SNPrs7749054 TT (p=0.07, OR=2 (1-3.6) and for rs2064501 CC (p=0.06, OR=2.7 1-7.3)). See Table 4.


TABLE 4
Extension of the associations detected in Chinese to Sudanese infected with
Sudanese sample
Controls
Cases
SNP
Position
Bin
Genotype
%
%
OR
95% CI
p
Univariate analysis
rs6570136
137536315
I
GG
8.3
24.5
3.1
1.3-7.2
0.006
rs7774663
137552586
I
CC + TT
45.5
66.7
1.7
  1-3.1
0.04
rs7749054
137542479
II
TT
0.2
rs202563
137503185
III
GG
21.8
34
1.6
0.9-3.0
0.09
rs276466
137508307
IV
AG + GG
0.25
rs11154915
137524675
V
TT
0.8
5.7
6.2
  1-35.3
0.07
rs2064501
137519516
VI
CC + TT
5.3
17
2.6
1.2-5.7
0.02
Multivariate analysis
rs6570136
I
GG
10
 3-34
0.0002
Model 1
rs2064501
VI
TT
3.4
1.2-9.4
0.018
rs11154915
V
TT
7.4
0.75-74  
0.09
(n = 189, 53 cases and 133 controls)

Likewise genotyping these same SNPs in the Brazilian sample (n=161, 119 mild HF and 42 severe HF) showed association with HF for SNP rs6570136 GG (p=0.0001, OR=6 (2.4-14.7)), rs7774663 TT (p=0.03, OR=3 (1.4-6.8)) and SNPrs7749054 TT (p=0.03, OR=2.8 (1.2-5.6), Furthermore rs11154915 TT,TC showed a trend for association with HF (p=0.14, OR=2.4 (0.9-6.5)).

See Table 5:


TABLE 5
Replication of the association in Brazilians infected with S. mansoni
Brazilian sample
Controls
Cases
SNP
Position
Bin
Genotype
%
%
OR
95% CI
p
Univariate
rs6570136
137536315
I
GG
11.5
35.6
4.2
1.8-10 
0.001
analysis
rs7774663
137552586
I
TT
24.5
44.2
2.4
1.2-5.1
0.02
rs7749054
137542479
II
TT
45.5
67.4
2.5
1.2-5.1
0.01
rs202563
137503185
III
AG + GG
73.5
86
0.13
rs276466
137508307
IV
AG + GG
26.5
41.9
2
0.9-4.3
0.07
rs11154915
137524675
V
CT + TT
74.3
87
2.3
0.9-6  
0.09
rs2064501
137519516
VI
CT + TT
52.8
66.7
0.15
Multivariate
rs6570136
I
GG
24.8
 3-205
0.003
analysis
rs2064501
VI
CT + TT
10.1
1.1-93 
0.04
rs11154915
V
CT + TT
2.3
0.8-6.9
0.14

Multivariate analysis performed in the Sudanese sample confirmed the independent associations of SNP rs6570136, 20564501 and 11154915. It was most remarkable that the high OR associated with rs11154915 was confirmed in the multivariate model. Furthermore subjects bearing the aggravating genotypes for both SNPs had in both models OR for HF greater than 25. The Multivariate analysis showed that the association of SNPs rs7749054 was lost in the presence of SNP rs6570136 confirming that this association was not independent of SNP rs6570136

In summary SNPs rs6570136 GG and rs7774663 TT, that belong to the same correlation bin were associated with HF, in all four samples tested. SNPrs11154915 TT, CT and rs2064501 CC showed a trend for association with HF in all samples; more important these trends were confirmed by multivariate analysis showing that these SNPs were acting independently of SNP rs6570136; taking into account these 2 SNPs increased the strength of the association of SNPrs6570136 with HF.

Example 4: Associations Between SNPs in IL22RA2 and Response to Anti-HCV Treatment

The inventors have performed their genetic analysis on 123 subjects (69 responders to treatment with ribavirin+IFN, 54 non responders) who were or have been infected with HCV genotypes 1 or 4. They tested at least one SNP in each of the 7 bins identified in IL22RA2 using Hapmap data. Univariate analysis showed associations with SNP rs2064501 (bin VI, p=0.013) and SNP rs1543509 (bin VII, p=0.012) but also suggested possible associations with SNPs rs7774663, rs6570136 (bin I, p<0.13), SNP rs77449054 (bin II, p=0.1), SNP rs202563 (bin III, p=0.07), SNP rs28366 (bin IV p=0.15), and SNP rs2064501 (bin VI, p=0.2). This high number of SNPs in possible associations with response to treatment could be due to correlations between the tested SNPs, it also suggested that the different SNPs could exert confounding effects on each others. Then a step by step multivariate analysis was undertaken.

Testing all SNPs two by two indicated that the association of SNP rs202563 and rs6570136 with response to treatment were equivalent but that SNPs rs276466 and rs28366 were clearly excluded from the regression model by SNP rs6570136. All tests showed that the association of SNP rs1154915 with response to treatment was enhanced by the presence of other SNPs (like SNP rs6570136 or SNP rs2064501 or SNP rs1543509) in the regression model. The association of rs6570136 with response to treatment was lost in the presence of SNPs rs2064501 or rs1543509 but this association was regained when SNP rs11154915 was added to the model (3 SNPs in the model). This is due to the strong linkage disequilibrium between SNP rs11154915 and SNP rs6570136 (or any SNPs in bin I), as a consequence SNP rs1154915 TT responder genotype is 100% associated with bin I's non responder genotypes. So the model must include at least 3 SNPs (rs11154915 (p=0.03), rs7774663 (or rs6570136, p=0.03) and SNP rs2064501 (p=0.001). Finally SNP rs1543509 and SNPs from bin I (p=0.15) also enter in this model.

In summary the inventors have found that SNPs that belong to four different bins in IL22RA2 are independently associated with the response to treatment. Importantly, these results that were obtained testing TagSNPs, can be extended to any SNP in the same bins. Then it is expected that most if not all SNPs in bins I, V, VI and VII are genetic markers response to IFN+ribavirin treatment. It can also be seen that 3 of these identified bins were associated with fibrosis progression (SNPS in bin VII have not been tested on fibrosis yet). Interestingly, most genotypes that aggravate hepatic fibrosis are associated with a better response to treatment.

REFERENCES

  • Bedossa P., Poynard, T. The METAVIR cooperative study group. An algorithm for the grading of activity in chronic hepatitis C, Hepatology 1996; 24:289-293.
  • Dessein, A. J., D. Hillaire, N. E. Elwali, S. Marquet, Q. Mohamed-Ali, A. Mirghani, S. Henri, A. A. Abdelhameed, O. K. Saeed, M. M. Magzoub, and L. Abel. 1999. Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am J Hum Genet 65:709.
  • EASL Clinical Practice Guideline: Management of hepatitis C virus infection, J. Hepatol. 2011; 55:245-264
  • Fried M W et al; N Engl J. Med. 2002; 347(13):975-82
  • Mohamed-Ali Q, Elwali N E, Abdelhameed A A, Mergani A, Rahoud S, Elagib K E, Saeed O K, Abel L, Magzoub M M, Dessein A J. Susceptibility to periportal (Symmers) fibrosis in human schistosoma mansoni infections: evidence that intensity and duration of infection, gender, and inherited factors are critical in disease progression. J Infect Dis. 1999 October; 180(4):1298-306. PMID: 10479161
  • Parkes J, Guha I N, Roderick P et al. Performance of serum marker panels for liver fibrosis in hepatitis C. J Hepatol 2006; 44: 462-474.
  • Sebastiani G, Vario A, Guido M et al. Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C. J Hepatol 2006; 44: 686-693.
  • Testino G et al; Hepatogastroenterology 2011; 58(106):536-8
  • Ziol M, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005; 41:48-54.

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caggttagta ctgaattatg ttttagcttc agaagggggt ttgtggaaaa cttaatttaa 3360

caaattgctg cttacaaatt gatgacaatg gaaaagctgt catggaaatc actgccagga 3420

tgcggaagtt agctcatgtt ctggttcaga catggtctgg ttggaacccg agttcactct 3480

ttggaggacg gttttcatgg tttggaggct ttaaaactgt aatactaggc tttgtggcca 3540

taaaaggtgg atgcctactg cttccctgtc tcttgccatt tctaatcgga agcatccaat 3600

ccaccataga ctcaatggta gacagacata ccaccatccg aataaaggct ctgcaaaagt 3660

accaactggt atcccaagat gagtatgtac ccactcaaga agaaatagct aactgtggtg 3720

ctctttatta atctacattt gtgtcgagca ccaaaagggg gaaatgaaga aggaattaat 3780

gaaatcaact ataacctaag agtagtagta atacaaattt taaaatcctt ttaaagttcc 3840

tgcaaaatgt gacccctgcc ttacattcac gttaaaaggg aatattaaca gcctgtcttc 3900

tctctgtgga cagtggacct tatctatact ccccaactcc acattcctca aagtttatta 3960

caggcccagt gagttcctgc atgactgcag ggtcacaaga 4000

<210> SEQ ID NO: 2

<211> LENGTH: 1001

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (501)..(501)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 2

taactgttga aattgggtgt caggtttatt atactctact tttgtatgta cttaaaattg 60

ttcataacaa agaaaaaaga tttttaaagt ttatctacaa gatgtggcca gacacggtgg 120

ctcacacctg taatctcagc actttggaag gcggaggtgg gtggatcatt tgaggtgtgg 180

agttccagac cagcctggcc aacatggtgc aaccccgtct gtactaaaaa tacaaaaatt 240

agccaggcgt gacggtgtgt gcctgtaatc ccagctactc agtggggctg aggcaggaga 300

attgcttgag tcaaggaggt gaggtttgca gtgagccgag atcgcgccac tgcgctccag 360

tctgggcagc gataaagcga gagtccatct caaaaaaata aataaataaa taaataaagt 420

ttacttacca gatgctgtct tccttttggt aattttaatg ccattttagt gtcaataata 480

agatctaata attatgggac rccatgttat gtttttccca tattttgtct ttgttaatcc 540

tcttatgaag tctaggagat tggtattatt attcatttga tgttacagat gaagaaactg 600

agacatagat agagaggtgg agagaacttg accagggctc tatagcgagt agtggtaaag 660

tgagggctga aatcagatct ggttagcctc agggcctgag gagtattatg aaactcctct 720

tgtgttattc tttgcttgta atagacattc cataaaggga tagaatgatg tcaaagaaca 780

tttgtccatt ggcttctcga atcgtttatt cagtcaaaca aatgtttatt gagcaactgt 840

tatatgccag gcactgtgtt agacatcggg gatgcagaaa tgaacaagac tacagagcca 900

gccctcaggg aaccaacagc attttcttca accaggtctt ggtagcaaag ggctaagtgt 960

ttcttattgt ttttcagaga agtgtttaaa aactggtgtt c 1001

<210> SEQ ID NO: 3

<211> LENGTH: 818

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (501)..(501)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 3

ccatgggaag gattccaacc ttcttccaca tccatgttcc ttgcttagcc caacaagacc 60

ctggcagagg ctcctgccca agggccatgc tgggccttgg gctcccctct cggcccttag 120

ctggctcctt gtcctctgag ctgcacttgt tccagcctga ggcatccctc cctcccaccc 180

ttcatccaca agaccccagc yctgcctcct caatgtttta tttgcattct gagttcctac 240

tatattgtat tcccaagaca tatctcttct aaatttctaa attacagtaa aacaacttct 300

aaatttcatg tgtgatatgg tttggctgtg tccccaccaa aatcttgtct tgcattgtag 360

cttccataat ccccatatat tgtgggaggg acctggtggg aggtaaatga atcatggggg 420

tgtttttttc ccatgctgtt ctcatgatag tgaataagtc ttacaagatc tgatgatttt 480

ataaagggca gttcccctgc acacatctct tgcctgccac catgtaagac gtgcctttgc 540

ttctcctcct tctgccatga ttgtgaggcc tacccagtca tggggaactg ttaatccatt 600

aaacctcttt ttatttataa attacccagt cttgggtatg tctttattag aagtgtgaga 660

aaggactaat acactgtgcc tcagtttcct cactggaaaa aaatgtataa tactagtctt 720

accagatagc taggagtgtc aataagagaa actttgccaa ccatctgcct atagtagagg 780

ctcaggcgca ttagttctcc ctcccatttc tttccact 818

<210> SEQ ID NO: 4

<211> LENGTH: 7142

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1706)..(1706)

<223> OTHER INFORMATION: k = g or t

<400> SEQENCE: 4

tgagcagggg gcacagcaaa gccccaaggc tgaggccaga tgaaggagca ggaggcaatg 60

tggctggaga ggagggagca aggggcagag tgttggtggt gaggtcaggg gcccagcagc 120

ctgatccagg ggacttgaac aggatggaag gactttgggt gcgttctgaa gaaggggaag 180

ccactggaag gcattaagta gaaaaaattg gaagtgagag taattatatg tgaaagttgt 240

tagagtcaca atggagtgac gatgaggcag gacaggtagt caaggaagta agtgcagtta 300

acacaatgag ccccagtatt cgcattgtaa tccagctcat gcaagcacag ctatctcctg 360

cagggaatat ttcccataga cagcatttgc actttgattt tacctcttct caaacggacc 420

ctgttctcat gataatagta aaaaacacac ccctaggtgg agatttaaga tgctgatgaa 480

ttatgagatg tatgaacaag catgtacagc tactgcacat gtgcacccag aggaccaccg 540

aggacatgct tactagcaac accttttctc accctcttat gaataatcat gtaagagtcc 600

cataaaagga tttctccagc aataatcagt gctgtccatt cagtggctca tgcctgtaac 660

ccagcacttt gggaggccga ggtgggtgga tcacctgagg tcaggagttt gagaccagcc 720

tggtcaacat ggtgaaacct cgtttctatt aaaaatacaa aaaaagtagc caggtgtaat 780

ggcacatgcc tgtaatccca gctacttggg aggctgaagc aggagaactg attgaacctg 840

ggaggtggag gttgcagtga gtcatgactg tgccactgca ctccagccaa cagagtaaga 900

ctctgttccc cctcggcccc ctgcaaaaaa aaataataac aatgataaga ggcaagatca 960

atggccacca aaattttatt ttttcccata gcgttgctgg ggtggcatgg ctgcctgccc 1020

tgggttcatc ctgtccctaa gtggaactcc ctatggctga gggactcaga atcaaatgac 1080

ttatagccaa ttaaatgttc tagtccagat gcccaattaa atgggcatgg acagacattc 1140

attagccttt aaattatttt ctaagtaaaa agtcaacaaa caaaaagtta aaggtgaggt 1200

tacaaaactg acttttcttt aacttctatg ctactgtaat cttgggtttt gttatggact 1260

tatagcaatt atttatacaa aacataagaa ttgttctgaa aaaattaaaa aatatatacc 1320

tgcatggctc ataactggaa atattatacc aggaggcttt gtcacttggt atctttatcc 1380

ttttacttat tattttcttt taattctaca ggaagcagta aattctttat ggttggagtg 1440

gatgaagagg tgccatgtaa tagctcagaa ggcaaagtcc cttgttttac cagctgttta 1500

ggcatccatg tactcatcct tgatttgaag ggtttgagtt aattctatcc ttccaaatca 1560

gcccttacaa tctcacgtgc ccacctcttc tgcaacagtc tctgggccta gagggaggac 1620

gcttgcaata caggattttt tgcatgttcc cagtggctcc accccattct cccagtgcac 1680

atgcaggccc ttagtctgaa cccackctac attgatttat ttcccttact gagcatgtgt 1740

taagggatgg aatttttcac catgggcatg tttaggcaag ccccctgtac acaatgtcct 1800

ggatggcatt tggctgtctt ctgcctctat cattccccca tctaaaagag tacatctaac 1860

tgccattaga ataaggataa gaagaaagac aaagacccat cttaactgct ttctgctgac 1920

agagggcact gttttggaaa gacagcagtt gggtctccct cagaggccta tctaagggta 1980

tctggtaaaa gggaccatca ttcgaggctc tggttgcata actgtttgga gtttgagggc 2040

ctgaaggcga gaagagacaa accaggttat tagaagacat gtaccaaaat gaaatggggg 2100

aagggtaagg acagttcaaa aatcctgagg ctgctgacat gcccagataa ctggtagctg 2160

tagttgtgcc tgctaagatt tgggtgcatg ggacttggct ttggttagct cccgtagttt 2220

attttcccaa aaaagaaacc tctgggttat gggcacccta tttactccca ttatctggca 2280

ggatttgtag gataattgtt cagaactaga atactgttcc agatttttac attacccatg 2340

ccttttgttt cttctgagct gcagccagag atcactggtt agttcacagg aataagcagg 2400

gttaatttaa aatgtaggca aaaaacttaa aaacaactaa tgagtctaga atttaatgac 2460

aaatgtatga taagttttga aacataattt ctttctcccc agtcctcatt tttgttaaaa 2520

acaaatcata ataggagtga gttgtttgta aaataaactt tagtcttaca cttggtctgc 2580

ttatttgcac aaagtacaac aagaataatt atttttacat aggcttttta aattggcttt 2640

gatggaactc tgttccacaa ggaatttcag ataggacttc ataaaaatga gcccagccat 2700

gggtttgtac cctctaatac ctatgagttg ggtgaattgc tctcttcttg aggtcccaag 2760

aatatgcggt tcctggccct gttagaaagt gacattcttt actcactaca ggttagggaa 2820

cctgtatggg gactgtgtag acaaagtatg aggctggttt acccaagggg cttttattgg 2880

ctctgcaagt tgagcttgat tccttaaagg gaaacatacc cttccagtca aagttacagt 2940

tactggttgg taaagttaaa gttacagcta ctggttgcta aagcaaccag tttctccaat 3000

tgcatcctgt tgcaaaagaa agtggattct tactgcactg atgcaaataa ccgtattgcc 3060

ctaagttaag aatactcaca gatagtttcc aaattctaga ggaagcaggc agagagaaaa 3120

aaaagtgcta aattttgttc ataggagtct gcattactca attattaaag attgtgtata 3180

gctcaaaaaa aaagatcagc actgttttaa gctaaagttt aaaaaagatt acttcaattt 3240

tctattagtt cagtctgttc agttaactct tgttctgctt gatatttgtg aacatttcag 3300

ctcttcatga gtcctgtacg tttttccatt attccaatgt cacaatctcc aaagttatca 3360

gaaacctgca tttgagagca cctgttacgt ttctatagct gattataaat cctatttgaa 3420

gaagatcaaa acaaaacaat ggtctgtgaa tagcaaaatg tccatggtag ttacagtcaa 3480

aaacacaatt gacaaagaaa ttttgttatc tctgtggctt ataatcacct aacataacac 3540

ctttaattgt gagtgatagc atatacttag atattagaat tttagaaatc ccatacagtt 3600

ttggagcata tattattatt cactaaaata taacccaaag aagattaaat atcattttgg 3660

caatcccatg tacataaatt tgtcaggtaa tcctatttac ctctcttctg gatgctccag 3720

ggatgctagg ggtcaggaaa gacaaccttg aagctgacat ttgattttgg gaagcccatt 3780

aaatatgtta gaggtttaaa acaatgttat gaagtagaat tccagattac cataaattac 3840

ttattttgcc aaaatgatga ctcaaaaatt ttaaaacaag ccaaaaactt ttactcattt 3900

agagggaaga cttagatttc caaagaattt gtctcctgtc ttcactttca tttccttggc 3960

agtctatctg gaagacaaac tgaaatattt aattatcctt tactattaca tgaaaatctt 4020

atacaaggga gagaaagcca aattttaccc tcacattagt ttactattaa tgtcaacccc 4080

aattttttaa tgaaacctta tagacaattc tatccaatct taaccagttt gatcatgagg 4140

taagattcct gtaagccttt tataaccttt tacaaattac taatttacta atctgctaaa 4200

gagcagatta gggctttaag aaaaccttgt tgtgctttca tttcaatgct cagtttgtag 4260

aaaaaccata taatagagtt ttggatttaa tcaatgttca cacacagaat ttcttttgca 4320

agattaattt ttagaaacct cccacaactt gtttaaacct ttagtttatc ttatctaatt 4380

tataatagtc ctttaacctt aggcaaaaac ttacatttcc atgcattctt ataatctttg 4440

actaataaca cattttactg ttcttacata ccttgcatgt aaatctattt tcagtggtct 4500

caattacatg ttataatggt acctcttagc actttttaat tttagtttaa aacctggtaa 4560

gtcgttttaa ttacgcacta ggtgctgata aagtttgatt ccttccagca taattaaggg 4620

tgtggttaat tccatatgtc cctgtgcctt accaagttgt aaagcaggca gattgaacag 4680

ttttcaaagg caaaagaagc cgtttacaac cttaaaacat ttagccacct agtgcctgac 4740

ttgcataatt tagaccagct atttacattt taagaacatt tgcattttat caattatctt 4800

taagactact tttatttctc agagattaaa gtcacaagaa ctaaaaggca ttatagcttt 4860

tatctttcct ccaaaaatat ttgatcttag tgctgatttt tctttaagcc aattaattag 4920

agctcttttt tataactaca cagatggaga agaagattga gtgttataag atttttcatt 4980

tgcccatctc ctaattggat tcttggtctc tgggtgggac cctttaagag cagggctaag 5040

aaagcatgca gtttattttc tttttttctt tttcttttct ttttttttga gaaagagttt 5100

cactcttgtt gcccaggctg gagtgcaatg gtgcgatctc agctcactgc aacctctgcc 5160

tcccaggttc aagcgattct cttacctcag cctcccaagt ggctgcatgc agtttctagg 5220

gcctaataaa caggcatagc tggaaaacaa aaacggattt tgagagcgat ctatttgcct 5280

ctaattcctg gggttccatg aggaaaacag aggtttctcc caaaatggaa tccatggtgc 5340

cttttctgtt tttaccaagc agccctatgc catcagaaat tatcttaggg cctctcatgt 5400

gcgcattaac actggcaaga caaggtggag aaaagtaatt cagtcaactg agaaaaaaat 5460

ctttttccag caaaacaaga tccaagaaga gaaaaacata aaggcctttc aaatatacgt 5520

atagcttgga tatccacttt taattaagct gagctctctt taagaaagtc cttttaaatc 5580

ccacattacc tgacttcagc catgccaagc agccaatatt tctggctttg gaagtttatc 5640

aaaagaacct caaggttcaa ccaacaagcc tcaattaaga cacgcgaagc acaccagatt 5700

ggctacacct taagaccagc ctcataaaac ctttttcact aatggaaact ttacagggaa 5760

tatcaacagt gatccttatc attcttttca ccagtttaca cagggagaga gaggccaaaa 5820

gtctgactgg ttaaaaaact tttatccttt tgctggcatg tcatgcttct gggttccctt 5880

cccctgagct caattctaag ccaaccagtt taaggtttgg gaaattaact tttctcagtt 5940

tggaggatgc atcctatggg aatgtccttt agtacaggga cacagtcacc catctgtgaa 6000

gagaggacaa aggaggaaaa agtaaaaaaa gatttttttc aaaggctccc caggggttca 6060

ggatgcattt gaaaggggga cagattgaag atgaatggct actcatctag aaagagggga 6120

gccagacatc cctggttcct ttctctttct aggaaatagc cagggtatgt gagggaaaga 6180

aggaacaagc atccattttc cttcttccgt ccttatgtcc ccaagtcctg acaacctcga 6240

cagggtgcca cccatgggtg ccaatacggt tctcacccat ggtaacaggg gacctagtgg 6300

atgggattat ccactgttac ccacaaactg tctttccccc tgctctcaat agccttcaag 6360

tgccctagac ctcatttagg ccattgatac tagtatgacc tttatccatg aaacaagagg 6420

cttggcttaa ttgtcaggaa ttagtcatgc tcacctatac tgtgcttttt aatttttgtt 6480

gttgtctgcc tctggatccc tccgatgcag ttatctttcc tagggcttct acatgaagct 6540

tggaattgag tttgggacaa aagaactgcc tcagtaggtg ggtgcatgga ctcatcaatc 6600

cccaggtgtc cctcaccagt ctggctgctg ccgccttatc ataagctgaa ggctaaggtg 6660

caactgtgaa attaggtcct tctcaaacaa gggagggaaa atggtgtcct gtgaattagg 6720

gtcctggtct aataagatgc cttccaaaag gaagaaaact tctggcacag agaagacccc 6780

tctacccgca gggctgtgtt attaggttgg tgcgaaagca attgtggtgc ccatcattct 6840

aagtaatgac aaaaaccaca actactttca caccagccta ctaactcatg acttggtgga 6900

caaaagaaaa taacaacaac aacaacagct taaatgcagg gctgtgttta ctgctgacaa 6960

ggtggagaaa agaaaaatat gcctgagaaa tgcaaatgta tttctccaac aggcagagaa 7020

acttaattgc tattgcactg agctggaccc cttggcttgg ggtggggaag actctgtgga 7080

tacatggcag gggacactgg ccagttggct gcatggggcc caggcccctg agatcaccct 7140

gg 7142

<210> SEQ ID NO: 5

<211> LENGTH: 7142

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1807)..(1807)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 5

gaaggagcag gaggcaatgt ggctggagag gagggagcaa ggggcagagt gttggtggtg 60

aggtcagggg cccagcagcc tgatccaggg gacttgaaca ggatggaagg actttgggtg 120

cgttctgaag aaggggaagc cactggaagg cattaagtag aaaaaattgg aagtgagagt 180

aattatatgt gaaagttgtt agagtcacaa tggagtgacg atgaggcagg acaggtagtc 240

aaggaagtaa gtgcagttaa cacaatgagc cccagtattc gcattgtaat ccagctcatg 300

caagcacagc tatctcctgc agggaatatt tcccatagac agcatttgca ctttgatttt 360

acctcttctc aaacggaccc tgttctcatg ataatagtaa aaaacacacc cctaggtgga 420

gatttaagat gctgatgaat tatgagatgt atgaacaagc atgtacagct actgcacatg 480

tgcacccaga ggaccaccga ggacatgctt actagcaaca ccttttctca ccctcttatg 540

aataatcatg taagagtccc ataaaaggat ttctccagca ataatcagtg ctgtccattc 600

agtggctcat gcctgtaacc cagcactttg ggaggccgag gtgggtggat cacctgaggt 660

caggagtttg agaccagcct ggtcaacatg gtgaaacctc gtttctatta aaaatacaaa 720

aaaagtagcc aggtgtaatg gcacatgcct gtaatcccag ctacttggga ggctgaagca 780

ggagaactga ttgaacctgg gaggtggagg ttgcagtgag tcatgactgt gccactgcac 840

tccagccaac agagtaagac tctgttcccc ctcggccccc tgcaaaaaaa aataataaca 900

atgataagag gcaagatcaa tggccaccaa aattttattt tttcccatag cgttgctggg 960

gtggcatggc tgcctgccct gggttcatcc tgtccctaag tggaactccc tatggctgag 1020

ggactcagaa tcaaatgact tatagccaat taaatgttct agtccagatg cccaattaaa 1080

tgggcatgga cagacattca ttagccttta aattattttc taagtaaaaa gtcaacaaac 1140

aaaaagttaa aggtgaggtt acaaaactga cttttcttta acttctatgc tactgtaatc 1200

ttgggttttg ttatggactt atagcaatta tttatacaaa acataagaat tgttctgaaa 1260

aaattaaaaa atatatacct gcatggctca taactggaaa tattatacca ggaggctttg 1320

tcacttggta tctttatcct tttacttatt attttctttt aattctacag gaagcagtaa 1380

attctttatg gttggagtgg atgaagaggt gccatgtaat agctcagaag gcaaagtccc 1440

ttgttttacc agctgtttag gcatccatgt actcatcctt gatttgaagg gtttgagtta 1500

attctatcct tccaaatcag cccttacaat ctcacgtgcc cacctcttct gcaacagtct 1560

ctgggcctag agggaggacg cttgcaatac aggatttttt gcatgttccc agtggctcca 1620

ccccattctc ccagtgcaca tgcaggccct tagtctgaac ccacgctaca ttgatttatt 1680

tcccttactg agcatgtgtt aagggatgga atttttcacc atgggcatgt ttaggcaagc 1740

cccctgtaca caatgtcctg gatggcattt ggctgtcttc tgcctctatc attcccccat 1800

ctaaaaragt acatctaact gccattagaa taaggataag aagaaagaca aagacccatc 1860

ttaactgctt tctgctgaca gagggcactg ttttggaaag acagcagttg ggtctccctc 1920

agaggcctat ctaagggtat ctggtaaaag ggaccatcat tcgaggctct ggttgcataa 1980

ctgtttggag tttgagggcc tgaaggcgag aagagacaaa ccaggttatt agaagacatg 2040

taccaaaatg aaatggggga agggtaagga cagttcaaaa atcctgaggc tgctgacatg 2100

cccagataac tggtagctgt agttgtgcct gctaagattt gggtgcatgg gacttggctt 2160

tggttagctc ccgtagttta ttttcccaaa aaagaaacct ctgggttatg ggcaccctat 2220

ttactcccat tatctggcag gatttgtagg ataattgttc agaactagaa tactgttcca 2280

gatttttaca ttacccatgc cttttgtttc ttctgagctg cagccagaga tcactggtta 2340

gttcacagga ataagcaggg ttaatttaaa atgtaggcaa aaaacttaaa aacaactaat 2400

gagtctagaa tttaatgaca aatgtatgat aagttttgaa acataatttc tttctcccca 2460

gtcctcattt ttgttaaaaa caaatcataa taggagtgag ttgtttgtaa aataaacttt 2520

agtcttacac ttggtctgct tatttgcaca aagtacaaca agaataatta tttttacata 2580

ggctttttaa attggctttg atggaactct gttccacaag gaatttcaga taggacttca 2640

taaaaatgag cccagccatg ggtttgtacc ctctaatacc tatgagttgg gtgaattgct 2700

ctcttcttga ggtcccaaga atatgcggtt cctggccctg ttagaaagtg acattcttta 2760

ctcactacag gttagggaac ctgtatgggg actgtgtaga caaagtatga ggctggttta 2820

cccaaggggc ttttattggc tctgcaagtt gagcttgatt ccttaaaggg aaacataccc 2880

ttccagtcaa agttacagtt actggttggt aaagttaaag ttacagctac tggttgctaa 2940

agcaaccagt ttctccaatt gcatcctgtt gcaaaagaaa gtggattctt actgcactga 3000

tgcaaataac cgtattgccc taagttaaga atactcacag atagtttcca aattctagag 3060

gaagcaggca gagagaaaaa aaagtgctaa attttgttca taggagtctg cattactcaa 3120

ttattaaaga ttgtgtatag ctcaaaaaaa aagatcagca ctgttttaag ctaaagttta 3180

aaaaagatta cttcaatttt ctattagttc agtctgttca gttaactctt gttctgcttg 3240

atatttgtga acatttcagc tcttcatgag tcctgtacgt ttttccatta ttccaatgtc 3300

acaatctcca aagttatcag aaacctgcat ttgagagcac ctgttacgtt tctatagctg 3360

attataaatc ctatttgaag aagatcaaaa caaaacaatg gtctgtgaat agcaaaatgt 3420

ccatggtagt tacagtcaaa aacacaattg acaaagaaat tttgttatct ctgtggctta 3480

taatcaccta acataacacc tttaattgtg agtgatagca tatacttaga tattagaatt 3540

ttagaaatcc catacagttt tggagcatat attattattc actaaaatat aacccaaaga 3600

agattaaata tcattttggc aatcccatgt acataaattt gtcaggtaat cctatttacc 3660

tctcttctgg atgctccagg gatgctaggg gtcaggaaag acaaccttga agctgacatt 3720

tgattttggg aagcccatta aatatgttag aggtttaaaa caatgttatg aagtagaatt 3780

ccagattacc ataaattact tattttgcca aaatgatgac tcaaaaattt taaaacaagc 3840

caaaaacttt tactcattta gagggaagac ttagatttcc aaagaatttg tctcctgtct 3900

tcactttcat ttccttggca gtctatctgg aagacaaact gaaatattta attatccttt 3960

actattacat gaaaatctta tacaagggag agaaagccaa attttaccct cacattagtt 4020

tactattaat gtcaacccca attttttaat gaaaccttat agacaattct atccaatctt 4080

aaccagtttg atcatgaggt aagattcctg taagcctttt ataacctttt acaaattact 4140

aatttactaa tctgctaaag agcagattag ggctttaaga aaaccttgtt gtgctttcat 4200

ttcaatgctc agtttgtaga aaaaccatat aatagagttt tggatttaat caatgttcac 4260

acacagaatt tcttttgcaa gattaatttt tagaaacctc ccacaacttg tttaaacctt 4320

tagtttatct tatctaattt ataatagtcc tttaacctta ggcaaaaact tacatttcca 4380

tgcattctta taatctttga ctaataacac attttactgt tcttacatac cttgcatgta 4440

aatctatttt cagtggtctc aattacatgt tataatggta cctcttagca ctttttaatt 4500

ttagtttaaa acctggtaag tcgttttaat tacgcactag gtgctgataa agtttgattc 4560

cttccagcat aattaagggt gtggttaatt ccatatgtcc ctgtgcctta ccaagttgta 4620

aagcaggcag attgaacagt tttcaaaggc aaaagaagcc gtttacaacc ttaaaacatt 4680

tagccaccta gtgcctgact tgcataattt agaccagcta tttacatttt aagaacattt 4740

gcattttatc aattatcttt aagactactt ttatttctca gagattaaag tcacaagaac 4800

taaaaggcat tatagctttt atctttcctc caaaaatatt tgatcttagt gctgattttt 4860

ctttaagcca attaattaga gctctttttt ataactacac agatggagaa gaagattgag 4920

tgttataaga tttttcattt gcccatctcc taattggatt cttggtctct gggtgggacc 4980

ctttaagagc agggctaaga aagcatgcag tttattttct ttttttcttt ttcttttctt 5040

tttttttgag aaagagtttc actcttgttg cccaggctgg agtgcaatgg tgcgatctca 5100

gctcactgca acctctgcct cccaggttca agcgattctc ttacctcagc ctcccaagtg 5160

gctgcatgca gtttctaggg cctaataaac aggcatagct ggaaaacaaa aacggatttt 5220

gagagcgatc tatttgcctc taattcctgg ggttccatga ggaaaacaga ggtttctccc 5280

aaaatggaat ccatggtgcc ttttctgttt ttaccaagca gccctatgcc atcagaaatt 5340

atcttagggc ctctcatgtg cgcattaaca ctggcaagac aaggtggaga aaagtaattc 5400

agtcaactga gaaaaaaatc tttttccagc aaaacaagat ccaagaagag aaaaacataa 5460

aggcctttca aatatacgta tagcttggat atccactttt aattaagctg agctctcttt 5520

aagaaagtcc ttttaaatcc cacattacct gacttcagcc atgccaagca gccaatattt 5580

ctggctttgg aagtttatca aaagaacctc aaggttcaac caacaagcct caattaagac 5640

acgcgaagca caccagattg gctacacctt aagaccagcc tcataaaacc tttttcacta 5700

atggaaactt tacagggaat atcaacagtg atccttatca ttcttttcac cagtttacac 5760

agggagagag aggccaaaag tctgactggt taaaaaactt ttatcctttt gctggcatgt 5820

catgcttctg ggttcccttc ccctgagctc aattctaagc caaccagttt aaggtttggg 5880

aaattaactt ttctcagttt ggaggatgca tcctatggga atgtccttta gtacagggac 5940

acagtcaccc atctgtgaag agaggacaaa ggaggaaaaa gtaaaaaaag atttttttca 6000

aaggctcccc aggggttcag gatgcatttg aaagggggac agattgaaga tgaatggcta 6060

ctcatctaga aagaggggag ccagacatcc ctggttcctt tctctttcta ggaaatagcc 6120

agggtatgtg agggaaagaa ggaacaagca tccattttcc ttcttccgtc cttatgtccc 6180

caagtcctga caacctcgac agggtgccac ccatgggtgc caatacggtt ctcacccatg 6240

gtaacagggg acctagtgga tgggattatc cactgttacc cacaaactgt ctttccccct 6300

gctctcaata gccttcaagt gccctagacc tcatttaggc cattgatact agtatgacct 6360

ttatccatga aacaagaggc ttggcttaat tgtcaggaat tagtcatgct cacctatact 6420

gtgcttttta atttttgttg ttgtctgcct ctggatccct ccgatgcagt tatctttcct 6480

agggcttcta catgaagctt ggaattgagt ttgggacaaa agaactgcct cagtaggtgg 6540

gtgcatggac tcatcaatcc ccaggtgtcc ctcaccagtc tggctgctgc cgccttatca 6600

taagctgaag gctaaggtgc aactgtgaaa ttaggtcctt ctcaaacaag ggagggaaaa 6660

tggtgtcctg tgaattaggg tcctggtcta ataagatgcc ttccaaaagg aagaaaactt 6720

ctggcacaga gaagacccct ctacccgcag ggctgtgtta ttaggttggt gcgaaagcaa 6780

ttgtggtgcc catcattcta agtaatgaca aaaaccacaa ctactttcac accagcctac 6840

taactcatga cttggtggac aaaagaaaat aacaacaaca acaacagctt aaatgcaggg 6900

ctgtgtttac tgctgacaag gtggagaaaa gaaaaatatg cctgagaaat gcaaatgtat 6960

ttctccaaca ggcagagaaa cttaattgct attgcactga gctggacccc ttggcttggg 7020

gtggggaaga ctctgtggat acatggcagg ggacactggc cagttggctg catggggccc 7080

aggcccctga gatcaccctg gggctggggc agcagctgtg gctcaatcct gcactggatg 7140

gc 7142

<210> SEQ ID NO: 6

<211> LENGTH: 7142

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (3512)..(3512)

<223> OTHER INFORMATION: k = g or t

<400> SEQENCE: 6

gaaggagcag gaggcaatgt ggctggagag gagggagcaa ggggcagagt gttggtggtg 60

aggtcagggg cccagcagcc tgatccaggg gacttgaaca ggatggaagg actttgggtg 120

cgttctgaag aaggggaagc cactggaagg cattaagtag aaaaaattgg aagtgagagt 180

aattatatgt gaaagttgtt agagtcacaa tggagtgacg atgaggcagg acaggtagtc 240

aaggaagtaa gtgcagttaa cacaatgagc cccagtattc gcattgtaat ccagctcatg 300

caagcacagc tatctcctgc agggaatatt tcccatagac agcatttgca ctttgatttt 360

acctcttctc aaacggaccc tgttctcatg ataatagtaa aaaacacacc cctaggtgga 420

gatttaagat gctgatgaat tatgagatgt atgaacaagc atgtacagct actgcacatg 480

tgcacccaga ggaccaccga ggacatgctt actagcaaca ccttttctca ccctcttatg 540

aataatcatg taagagtccc ataaaaggat ttctccagca ataatcagtg ctgtccattc 600

agtggctcat gcctgtaacc cagcactttg ggaggccgag gtgggtggat cacctgaggt 660

caggagtttg agaccagcct ggtcaacatg gtgaaacctc gtttctatta aaaatacaaa 720

aaaagtagcc aggtgtaatg gcacatgcct gtaatcccag ctacttggga ggctgaagca 780

ggagaactga ttgaacctgg gaggtggagg ttgcagtgag tcatgactgt gccactgcac 840

tccagccaac agagtaagac tctgttcccc ctcggccccc tgcaaaaaaa aataataaca 900

atgataagag gcaagatcaa tggccaccaa aattttattt tttcccatag cgttgctggg 960

gtggcatggc tgcctgccct gggttcatcc tgtccctaag tggaactccc tatggctgag 1020

ggactcagaa tcaaatgact tatagccaat taaatgttct agtccagatg cccaattaaa 1080

tgggcatgga cagacattca ttagccttta aattattttc taagtaaaaa gtcaacaaac 1140

aaaaagttaa aggtgaggtt acaaaactga cttttcttta acttctatgc tactgtaatc 1200

ttgggttttg ttatggactt atagcaatta tttatacaaa acataagaat tgttctgaaa 1260

aaattaaaaa atatatacct gcatggctca taactggaaa tattatacca ggaggctttg 1320

tcacttggta tctttatcct tttacttatt attttctttt aattctacag gaagcagtaa 1380

attctttatg gttggagtgg atgaagaggt gccatgtaat agctcagaag gcaaagtccc 1440

ttgttttacc agctgtttag gcatccatgt actcatcctt gatttgaagg gtttgagtta 1500

attctatcct tccaaatcag cccttacaat ctcacgtgcc cacctcttct gcaacagtct 1560

ctgggcctag agggaggacg cttgcaatac aggatttttt gcatgttccc agtggctcca 1620

ccccattctc ccagtgcaca tgcaggccct tagtctgaac ccacgctaca ttgatttatt 1680

tcccttactg agcatgtgtt aagggatgga atttttcacc atgggcatgt ttaggcaagc 1740

cccctgtaca caatgtcctg gatggcattt ggctgtcttc tgcctctatc attcccccat 1800

ctaaaagagt acatctaact gccattagaa taaggataag aagaaagaca aagacccatc 1860

ttaactgctt tctgctgaca gagggcactg ttttggaaag acagcagttg ggtctccctc 1920

agaggcctat ctaagggtat ctggtaaaag ggaccatcat tcgaggctct ggttgcataa 1980

ctgtttggag tttgagggcc tgaaggcgag aagagacaaa ccaggttatt agaagacatg 2040

taccaaaatg aaatggggga agggtaagga cagttcaaaa atcctgaggc tgctgacatg 2100

cccagataac tggtagctgt agttgtgcct gctaagattt gggtgcatgg gacttggctt 2160

tggttagctc ccgtagttta ttttcccaaa aaagaaacct ctgggttatg ggcaccctat 2220

ttactcccat tatctggcag gatttgtagg ataattgttc agaactagaa tactgttcca 2280

gatttttaca ttacccatgc cttttgtttc ttctgagctg cagccagaga tcactggtta 2340

gttcacagga ataagcaggg ttaatttaaa atgtaggcaa aaaacttaaa aacaactaat 2400

gagtctagaa tttaatgaca aatgtatgat aagttttgaa acataatttc tttctcccca 2460

gtcctcattt ttgttaaaaa caaatcataa taggagtgag ttgtttgtaa aataaacttt 2520

agtcttacac ttggtctgct tatttgcaca aagtacaaca agaataatta tttttacata 2580

ggctttttaa attggctttg atggaactct gttccacaag gaatttcaga taggacttca 2640

taaaaatgag cccagccatg ggtttgtacc ctctaatacc tatgagttgg gtgaattgct 2700

ctcttcttga ggtcccaaga atatgcggtt cctggccctg ttagaaagtg acattcttta 2760

ctcactacag gttagggaac ctgtatgggg actgtgtaga caaagtatga ggctggttta 2820

cccaaggggc ttttattggc tctgcaagtt gagcttgatt ccttaaaggg aaacataccc 2880

ttccagtcaa agttacagtt actggttggt aaagttaaag ttacagctac tggttgctaa 2940

agcaaccagt ttctccaatt gcatcctgtt gcaaaagaaa gtggattctt actgcactga 3000

tgcaaataac cgtattgccc taagttaaga atactcacag atagtttcca aattctagag 3060

gaagcaggca gagagaaaaa aaagtgctaa attttgttca taggagtctg cattactcaa 3120

ttattaaaga ttgtgtatag ctcaaaaaaa aagatcagca ctgttttaag ctaaagttta 3180

aaaaagatta cttcaatttt ctattagttc agtctgttca gttaactctt gttctgcttg 3240

atatttgtga acatttcagc tcttcatgag tcctgtacgt ttttccatta ttccaatgtc 3300

acaatctcca aagttatcag aaacctgcat ttgagagcac ctgttacgtt tctatagctg 3360

attataaatc ctatttgaag aagatcaaaa caaaacaatg gtctgtgaat agcaaaatgt 3420

ccatggtagt tacagtcaaa aacacaattg acaaagaaat tttgttatct ctgtggctta 3480

taatcaccta acataacacc tttaattgtg aktgatagca tatacttaga tattagaatt 3540

ttagaaatcc catacagttt tggagcatat attattattc actaaaatat aacccaaaga 3600

agattaaata tcattttggc aatcccatgt acataaattt gtcaggtaat cctatttacc 3660

tctcttctgg atgctccagg gatgctaggg gtcaggaaag acaaccttga agctgacatt 3720

tgattttggg aagcccatta aatatgttag aggtttaaaa caatgttatg aagtagaatt 3780

ccagattacc ataaattact tattttgcca aaatgatgac tcaaaaattt taaaacaagc 3840

caaaaacttt tactcattta gagggaagac ttagatttcc aaagaatttg tctcctgtct 3900

tcactttcat ttccttggca gtctatctgg aagacaaact gaaatattta attatccttt 3960

actattacat gaaaatctta tacaagggag agaaagccaa attttaccct cacattagtt 4020

tactattaat gtcaacccca attttttaat gaaaccttat agacaattct atccaatctt 4080

aaccagtttg atcatgaggt aagattcctg taagcctttt ataacctttt acaaattact 4140

aatttactaa tctgctaaag agcagattag ggctttaaga aaaccttgtt gtgctttcat 4200

ttcaatgctc agtttgtaga aaaaccatat aatagagttt tggatttaat caatgttcac 4260

acacagaatt tcttttgcaa gattaatttt tagaaacctc ccacaacttg tttaaacctt 4320

tagtttatct tatctaattt ataatagtcc tttaacctta ggcaaaaact tacatttcca 4380

tgcattctta taatctttga ctaataacac attttactgt tcttacatac cttgcatgta 4440

aatctatttt cagtggtctc aattacatgt tataatggta cctcttagca ctttttaatt 4500

ttagtttaaa acctggtaag tcgttttaat tacgcactag gtgctgataa agtttgattc 4560

cttccagcat aattaagggt gtggttaatt ccatatgtcc ctgtgcctta ccaagttgta 4620

aagcaggcag attgaacagt tttcaaaggc aaaagaagcc gtttacaacc ttaaaacatt 4680

tagccaccta gtgcctgact tgcataattt agaccagcta tttacatttt aagaacattt 4740

gcattttatc aattatcttt aagactactt ttatttctca gagattaaag tcacaagaac 4800

taaaaggcat tatagctttt atctttcctc caaaaatatt tgatcttagt gctgattttt 4860

ctttaagcca attaattaga gctctttttt ataactacac agatggagaa gaagattgag 4920

tgttataaga tttttcattt gcccatctcc taattggatt cttggtctct gggtgggacc 4980

ctttaagagc agggctaaga aagcatgcag tttattttct ttttttcttt ttcttttctt 5040

tttttttgag aaagagtttc actcttgttg cccaggctgg agtgcaatgg tgcgatctca 5100

gctcactgca acctctgcct cccaggttca agcgattctc ttacctcagc ctcccaagtg 5160

gctgcatgca gtttctaggg cctaataaac aggcatagct ggaaaacaaa aacggatttt 5220

gagagcgatc tatttgcctc taattcctgg ggttccatga ggaaaacaga ggtttctccc 5280

aaaatggaat ccatggtgcc ttttctgttt ttaccaagca gccctatgcc atcagaaatt 5340

atcttagggc ctctcatgtg cgcattaaca ctggcaagac aaggtggaga aaagtaattc 5400

agtcaactga gaaaaaaatc tttttccagc aaaacaagat ccaagaagag aaaaacataa 5460

aggcctttca aatatacgta tagcttggat atccactttt aattaagctg agctctcttt 5520

aagaaagtcc ttttaaatcc cacattacct gacttcagcc atgccaagca gccaatattt 5580

ctggctttgg aagtttatca aaagaacctc aaggttcaac caacaagcct caattaagac 5640

acgcgaagca caccagattg gctacacctt aagaccagcc tcataaaacc tttttcacta 5700

atggaaactt tacagggaat atcaacagtg atccttatca ttcttttcac cagtttacac 5760

agggagagag aggccaaaag tctgactggt taaaaaactt ttatcctttt gctggcatgt 5820

catgcttctg ggttcccttc ccctgagctc aattctaagc caaccagttt aaggtttggg 5880

aaattaactt ttctcagttt ggaggatgca tcctatggga atgtccttta gtacagggac 5940

acagtcaccc atctgtgaag agaggacaaa ggaggaaaaa gtaaaaaaag atttttttca 6000

aaggctcccc aggggttcag gatgcatttg aaagggggac agattgaaga tgaatggcta 6060

ctcatctaga aagaggggag ccagacatcc ctggttcctt tctctttcta ggaaatagcc 6120

agggtatgtg agggaaagaa ggaacaagca tccattttcc ttcttccgtc cttatgtccc 6180

caagtcctga caacctcgac agggtgccac ccatgggtgc caatacggtt ctcacccatg 6240

gtaacagggg acctagtgga tgggattatc cactgttacc cacaaactgt ctttccccct 6300

gctctcaata gccttcaagt gccctagacc tcatttaggc cattgatact agtatgacct 6360

ttatccatga aacaagaggc ttggcttaat tgtcaggaat tagtcatgct cacctatact 6420

gtgcttttta atttttgttg ttgtctgcct ctggatccct ccgatgcagt tatctttcct 6480

agggcttcta catgaagctt ggaattgagt ttgggacaaa agaactgcct cagtaggtgg 6540

gtgcatggac tcatcaatcc ccaggtgtcc ctcaccagtc tggctgctgc cgccttatca 6600

taagctgaag gctaaggtgc aactgtgaaa ttaggtcctt ctcaaacaag ggagggaaaa 6660

tggtgtcctg tgaattaggg tcctggtcta ataagatgcc ttccaaaagg aagaaaactt 6720

ctggcacaga gaagacccct ctacccgcag ggctgtgtta ttaggttggt gcgaaagcaa 6780

ttgtggtgcc catcattcta agtaatgaca aaaaccacaa ctactttcac accagcctac 6840

taactcatga cttggtggac aaaagaaaat aacaacaaca acaacagctt aaatgcaggg 6900

ctgtgtttac tgctgacaag gtggagaaaa gaaaaatatg cctgagaaat gcaaatgtat 6960

ttctccaaca ggcagagaaa cttaattgct attgcactga gctggacccc ttggcttggg 7020

gtggggaaga ctctgtggat acatggcagg ggacactggc cagttggctg catggggccc 7080

aggcccctga gatcaccctg gggctggggc agcagctgtg gctcaatcct gcactggatg 7140

gc 7142

<210> SEQ ID NO: 7

<211> LENGTH: 3609

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1609)..(1609)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 7

cagacagtca tgcaccccag ccaggaggga agggggaatg gggagatgct gtcttcctat 60

ccatcctaca catgtgccta tggccattgg gttgggagtg gaacaccccc aatattgtaa 120

aagaaaagat aggtgccatt acaatccccc taaaaagaag gaaaatgcca tagaaaagac 180

tgggttggac tgaggccgat gttcctgacc cctgagagca atggggggtt gaagggtggg 240

gtgcaatttc ccccatcctt agaaaacacc tgagaacaag aaagctcaga aacaaaaggg 300

aaagaaatgt tctgggttca cattttactc acccaggcaa tgtcagcttt ctcattataa 360

cttttggctt ttgatttttt ttttttaatt ttacaatctg gacaaatagt gttttaaata 420

cctttgtttt aaccccctca atttccattc tatttatttc atttcttaac aaccatccaa 480

agatttctat cacccttctg gggcgactcc tttgactctc ttttgccttt ctcatttttt 540

tttaaattac ctcaacattt tattaaggat ctgtaagacc cacaagggac agcaaatttg 600

atacaacttg tcaaacaatt gtatggttct gtcggagaaa tgtcacctgg gatgcctatg 660

taaaagggac ctctttaacc cccaaattta ccatgacctg ggtaataggc atataaagtg 720

ggagaatatc ctggtcatca taaagccagt accatgtggc ttgcttatga atcatatcta 780

ctgcttcatc tgggttactc cacttggcat tttataggga gagttgggca gtccctttct 840

tggggtaaac agactttaca gtggcattta tccagtccac tagggttgga tgttctctca 900

ggaataacct cctatgcatt tggatcactt atactcatta gagatttaat agtgagctgt 960

gggtcatgga tcaaactaaa gaagctcttt cactctgtag catttaaaat taaggattct 1020

atccttaaat tagttatttt taaatccatt atagtaaaag tgtctcagga agctgactat 1080

accaatctac aaaatggaac aattccttta cattatagcc tctggtttta atagttgttt 1140

tgccctgccc ctacatttac tatcttcttg gtaaccacag gtctcagagg taaactttgt 1200

tgccccggtt taatttatat ttttgtgagt agcttggatg ctagaggctt gagctgagac 1260

agacccactt ctggtcttgg tccactctta aggaccaacc caacactctt ttactctcat 1320

ttcagctttt acagataata accaaaggat gaaacatttt tcttccttat tagcttgcct 1380

tcccttatgc attcagggaa ctaactccct gggagtatga gtaggatcca tctctaattc 1440

cactggtaac ttttactttt agtaactgac tatagcccag ctgcagctcc ttaagatggg 1500

caaccacatg gctactcaag agtcaggatt tctcatttca caccctttta tttttttctt 1560

tatccattta gttttatcta tataattttt tcctttattt tagagtgayt cataaatagt 1620

ctctagaaaa aaattacatt ttctttagca aaaactagtt ccttgtgttt tcagaaacct 1680

caccaaaaac accttttatt cacctactag tttaagtctt attaactcaa attcccagtg 1740

gaaaaaaaac tcataggttt acttaattta aacattacat gacttattaa cccaaatccc 1800

cagtggggga aaaaagtaac ctaggtttac ttaatttaaa cataacatga ctttaagatt 1860

ttaaattact ggaaataatt gagattaaat ttaccaaatt aatcttacca aagattacta 1920

gtcatgtgag ctaaaaggca tctgagctag gttccatcag tctgataagc attaacattc 1980

tccaagccaa ttgattagag ctcttttgta ccacttgtta gtgaaatatc acttccacat 2040

ggcacatgta aacatgtaga tataacagac atatagaaaa cggcaggtcc aaaagatttt 2100

tcatttgcct cttttcaaaa attctctccc ctactttaga ttattaattt aaaaaagtta 2160

taaggccaaa caaaagttga aggagagagt taccatccta ggccttttca aaagcgaaaa 2220

aaggactgag atatcaattt gaataatttc aaaaagaaac attacagaat ttaaaaatta 2280

aaaactttgt gcattgagta actcaatatt ttaaataaaa tcttgttcta accaaatctt 2340

tagttattta ttagtgtatt tttttttgag acagagtctt gctcttgttg ctcaggctgg 2400

agtgcaatgg tgcgatctca gctcactgca acttctgcct cccaggttca agtgattctc 2460

ctgcctcagc ttcccaagta gctgggatta caggcacctg ccaccatgcc cagctaattt 2520

tttaattttt agtagagaca gggtttcacc atgttggcca ggctggtctc gaactcctga 2580

cctatatgat ctgctcgcct cggcctccca aagtgctagg attacaggcg tgagcaccgc 2640

acccagtcta gtgtattttt aacataaaag ttcaatttaa aaaaaagatt ataattttct 2700

gtaattatgg acaacttaat cacataacat ttgtataaat ttctttttta ctaactttat 2760

tatgacttac acagaccatt cacaacatgc ttggactttc tgctttgacc taagtgtcac 2820

tctttctgga ataactcggt cattttatct taggacaaaa attcaccaaa caatattttt 2880

ctcatacaaa attacttttc ttttaagctt tcttaccaaa aatacctctg tatatctata 2940

cttttcttta tattggtcta tttcctggtt cctttcacat tcttatttat acaggacttt 3000

taaataagct ttgaattaga caaaaattat ttacctttta ataagaacat attttaaaaa 3060

aagaataaaa tataattttt tgaattggaa aatacccaga tatttaatta aatatctatt 3120

attgaattta atataatttt atattctaaa ttatgacaag tttatttaca ggtatttatc 3180

cctttacatt tacctgatta ttttatttta atattttatg tagactatga aaactgtgat 3240

agtcatcatt taaagttatt tccctgtcaa tgatttttat agcctatgaa gttcaggtgt 3300

ttacctaagt aagaacctca ggattaaata tatggttatt ttaccaataa ttccaagttt 3360

agctgttttc attaaaccaa caatatttga tatcttgttt gtcaaaaact acacaagcaa 3420

agatcattct gttttgggtt ggtgtattag tctgttctca cattgttatt aaaaaatcct 3480

ggaattgggt aatctataaa gaaaagaggt ttaattggct tacagtttta caggctatat 3540

aggaagcata gcagcttttg cttggaaact tataatcatg gtgaaaggtg aaggtgaagc 3600

aggcatgtc 3609

<210> SEQ ID NO: 8

<211> LENGTH: 3659

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1659)..(1659)

<223> OTHER INFORMATION: w = a or t

<400> SEQENCE: 8

cagacagtca tgcaccccag ccaggaggga agggggaatg gggagatgct gtcttcctat 60

ccatcctaca catgtgccta tggccattgg gttgggagtg gaacaccccc aatattgtaa 120

aagaaaagat aggtgccatt acaatccccc taaaaagaag gaaaatgcca tagaaaagac 180

tgggttggac tgaggccgat gttcctgacc cctgagagca atggggggtt gaagggtggg 240

gtgcaatttc ccccatcctt agaaaacacc tgagaacaag aaagctcaga aacaaaaggg 300

aaagaaatgt tctgggttca cattttactc acccaggcaa tgtcagcttt ctcattataa 360

cttttggctt ttgatttttt ttttttaatt ttacaatctg gacaaatagt gttttaaata 420

cctttgtttt aaccccctca atttccattc tatttatttc atttcttaac aaccatccaa 480

agatttctat cacccttctg gggcgactcc tttgactctc ttttgccttt ctcatttttt 540

tttaaattac ctcaacattt tattaaggat ctgtaagacc cacaagggac agcaaatttg 600

atacaacttg tcaaacaatt gtatggttct gtcggagaaa tgtcacctgg gatgcctatg 660

taaaagggac ctctttaacc cccaaattta ccatgacctg ggtaataggc atataaagtg 720

ggagaatatc ctggtcatca taaagccagt accatgtggc ttgcttatga atcatatcta 780

ctgcttcatc tgggttactc cacttggcat tttataggga gagttgggca gtccctttct 840

tggggtaaac agactttaca gtggcattta tccagtccac tagggttgga tgttctctca 900

ggaataacct cctatgcatt tggatcactt atactcatta gagatttaat agtgagctgt 960

gggtcatgga tcaaactaaa gaagctcttt cactctgtag catttaaaat taaggattct 1020

atccttaaat tagttatttt taaatccatt atagtaaaag tgtctcagga agctgactat 1080

accaatctac aaaatggaac aattccttta cattatagcc tctggtttta atagttgttt 1140

tgccctgccc ctacatttac tatcttcttg gtaaccacag gtctcagagg taaactttgt 1200

tgccccggtt taatttatat ttttgtgagt agcttggatg ctagaggctt gagctgagac 1260

agacccactt ctggtcttgg tccactctta aggaccaacc caacactctt ttactctcat 1320

ttcagctttt acagataata accaaaggat gaaacatttt tcttccttat tagcttgcct 1380

tcccttatgc attcagggaa ctaactccct gggagtatga gtaggatcca tctctaattc 1440

cactggtaac ttttactttt agtaactgac tatagcccag ctgcagctcc ttaagatggg 1500

caaccacatg gctactcaag agtcaggatt tctcatttca caccctttta tttttttctt 1560

tatccattta gttttatcta tataattttt tcctttattt tagagtgatt cataaatagt 1620

ctctagaaaa aaattacatt ttctttagca aaaactagwt ccttgtgttt tcagaaacct 1680

caccaaaaac accttttatt cacctactag tttaagtctt attaactcaa attcccagtg 1740

gaaaaaaaac tcataggttt acttaattta aacattacat gacttattaa cccaaatccc 1800

cagtggggga aaaaagtaac ctaggtttac ttaatttaaa cataacatga ctttaagatt 1860

ttaaattact ggaaataatt gagattaaat ttaccaaatt aatcttacca aagattacta 1920

gtcatgtgag ctaaaaggca tctgagctag gttccatcag tctgataagc attaacattc 1980

tccaagccaa ttgattagag ctcttttgta ccacttgtta gtgaaatatc acttccacat 2040

ggcacatgta aacatgtaga tataacagac atatagaaaa cggcaggtcc aaaagatttt 2100

tcatttgcct cttttcaaaa attctctccc ctactttaga ttattaattt aaaaaagtta 2160

taaggccaaa caaaagttga aggagagagt taccatccta ggccttttca aaagcgaaaa 2220

aaggactgag atatcaattt gaataatttc aaaaagaaac attacagaat ttaaaaatta 2280

aaaactttgt gcattgagta actcaatatt ttaaataaaa tcttgttcta accaaatctt 2340

tagttattta ttagtgtatt tttttttgag acagagtctt gctcttgttg ctcaggctgg 2400

agtgcaatgg tgcgatctca gctcactgca acttctgcct cccaggttca agtgattctc 2460

ctgcctcagc ttcccaagta gctgggatta caggcacctg ccaccatgcc cagctaattt 2520

tttaattttt agtagagaca gggtttcacc atgttggcca ggctggtctc gaactcctga 2580

cctatatgat ctgctcgcct cggcctccca aagtgctagg attacaggcg tgagcaccgc 2640

acccagtcta gtgtattttt aacataaaag ttcaatttaa aaaaaagatt ataattttct 2700

gtaattatgg acaacttaat cacataacat ttgtataaat ttctttttta ctaactttat 2760

tatgacttac acagaccatt cacaacatgc ttggactttc tgctttgacc taagtgtcac 2820

tctttctgga ataactcggt cattttatct taggacaaaa attcaccaaa caatattttt 2880

ctcatacaaa attacttttc ttttaagctt tcttaccaaa aatacctctg tatatctata 2940

cttttcttta tattggtcta tttcctggtt cctttcacat tcttatttat acaggacttt 3000

taaataagct ttgaattaga caaaaattat ttacctttta ataagaacat attttaaaaa 3060

aagaataaaa tataattttt tgaattggaa aatacccaga tatttaatta aatatctatt 3120

attgaattta atataatttt atattctaaa ttatgacaag tttatttaca ggtatttatc 3180

cctttacatt tacctgatta ttttatttta atattttatg tagactatga aaactgtgat 3240

agtcatcatt taaagttatt tccctgtcaa tgatttttat agcctatgaa gttcaggtgt 3300

ttacctaagt aagaacctca ggattaaata tatggttatt ttaccaataa ttccaagttt 3360

agctgttttc attaaaccaa caatatttga tatcttgttt gtcaaaaact acacaagcaa 3420

agatcattct gttttgggtt ggtgtattag tctgttctca cattgttatt aaaaaatcct 3480

ggaattgggt aatctataaa gaaaagaggt ttaattggct tacagtttta caggctatat 3540

aggaagcata gcagcttttg cttggaaact tataatcatg gtgaaaggtg aaggtgaagc 3600

aggcatgtct tacatggctg gagaaggagg aagagaaggt tgttggggag gtgccacac 3659

<210> SEQ ID NO: 9

<211> LENGTH: 3876

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1876)..(1876)

<223> OTHER INFORMATION: k = g or t

<400> SEQENCE: 9

cagacagtca tgcaccccag ccaggaggga agggggaatg gggagatgct gtcttcctat 60

ccatcctaca catgtgccta tggccattgg gttgggagtg gaacaccccc aatattgtaa 120

aagaaaagat aggtgccatt acaatccccc taaaaagaag gaaaatgcca tagaaaagac 180

tgggttggac tgaggccgat gttcctgacc cctgagagca atggggggtt gaagggtggg 240

gtgcaatttc ccccatcctt agaaaacacc tgagaacaag aaagctcaga aacaaaaggg 300

aaagaaatgt tctgggttca cattttactc acccaggcaa tgtcagcttt ctcattataa 360

cttttggctt ttgatttttt ttttttaatt ttacaatctg gacaaatagt gttttaaata 420

cctttgtttt aaccccctca atttccattc tatttatttc atttcttaac aaccatccaa 480

agatttctat cacccttctg gggcgactcc tttgactctc ttttgccttt ctcatttttt 540

tttaaattac ctcaacattt tattaaggat ctgtaagacc cacaagggac agcaaatttg 600

atacaacttg tcaaacaatt gtatggttct gtcggagaaa tgtcacctgg gatgcctatg 660

taaaagggac ctctttaacc cccaaattta ccatgacctg ggtaataggc atataaagtg 720

ggagaatatc ctggtcatca taaagccagt accatgtggc ttgcttatga atcatatcta 780

ctgcttcatc tgggttactc cacttggcat tttataggga gagttgggca gtccctttct 840

tggggtaaac agactttaca gtggcattta tccagtccac tagggttgga tgttctctca 900

ggaataacct cctatgcatt tggatcactt atactcatta gagatttaat agtgagctgt 960

gggtcatgga tcaaactaaa gaagctcttt cactctgtag catttaaaat taaggattct 1020

atccttaaat tagttatttt taaatccatt atagtaaaag tgtctcagga agctgactat 1080

accaatctac aaaatggaac aattccttta cattatagcc tctggtttta atagttgttt 1140

tgccctgccc ctacatttac tatcttcttg gtaaccacag gtctcagagg taaactttgt 1200

tgccccggtt taatttatat ttttgtgagt agcttggatg ctagaggctt gagctgagac 1260

agacccactt ctggtcttgg tccactctta aggaccaacc caacactctt ttactctcat 1320

ttcagctttt acagataata accaaaggat gaaacatttt tcttccttat tagcttgcct 1380

tcccttatgc attcagggaa ctaactccct gggagtatga gtaggatcca tctctaattc 1440

cactggtaac ttttactttt agtaactgac tatagcccag ctgcagctcc ttaagatggg 1500

caaccacatg gctactcaag agtcaggatt tctcatttca caccctttta tttttttctt 1560

tatccattta gttttatcta tataattttt tcctttattt tagagtgatt cataaatagt 1620

ctctagaaaa aaattacatt ttctttagca aaaactagtt ccttgtgttt tcagaaacct 1680

caccaaaaac accttttatt cacctactag tttaagtctt attaactcaa attcccagtg 1740

gaaaaaaaac tcataggttt acttaattta aacattacat gacttattaa cccaaatccc 1800

cagtggggga aaaaagtaac ctaggtttac ttaatttaaa cataacatga ctttaagatt 1860

ttaaattact ggaaakaatt gagattaaat ttaccaaatt aatcttacca aagattacta 1920

gtcatgtgag ctaaaaggca tctgagctag gttccatcag tctgataagc attaacattc 1980

tccaagccaa ttgattagag ctcttttgta ccacttgtta gtgaaatatc acttccacat 2040

ggcacatgta aacatgtaga tataacagac atatagaaaa cggcaggtcc aaaagatttt 2100

tcatttgcct cttttcaaaa attctctccc ctactttaga ttattaattt aaaaaagtta 2160

taaggccaaa caaaagttga aggagagagt taccatccta ggccttttca aaagcgaaaa 2220

aaggactgag atatcaattt gaataatttc aaaaagaaac attacagaat ttaaaaatta 2280

aaaactttgt gcattgagta actcaatatt ttaaataaaa tcttgttcta accaaatctt 2340

tagttattta ttagtgtatt tttttttgag acagagtctt gctcttgttg ctcaggctgg 2400

agtgcaatgg tgcgatctca gctcactgca acttctgcct cccaggttca agtgattctc 2460

ctgcctcagc ttcccaagta gctgggatta caggcacctg ccaccatgcc cagctaattt 2520

tttaattttt agtagagaca gggtttcacc atgttggcca ggctggtctc gaactcctga 2580

cctatatgat ctgctcgcct cggcctccca aagtgctagg attacaggcg tgagcaccgc 2640

acccagtcta gtgtattttt aacataaaag ttcaatttaa aaaaaagatt ataattttct 2700

gtaattatgg acaacttaat cacataacat ttgtataaat ttctttttta ctaactttat 2760

tatgacttac acagaccatt cacaacatgc ttggactttc tgctttgacc taagtgtcac 2820

tctttctgga ataactcggt cattttatct taggacaaaa attcaccaaa caatattttt 2880

ctcatacaaa attacttttc ttttaagctt tcttaccaaa aatacctctg tatatctata 2940

cttttcttta tattggtcta tttcctggtt cctttcacat tcttatttat acaggacttt 3000

taaataagct ttgaattaga caaaaattat ttacctttta ataagaacat attttaaaaa 3060

aagaataaaa tataattttt tgaattggaa aatacccaga tatttaatta aatatctatt 3120

attgaattta atataatttt atattctaaa ttatgacaag tttatttaca ggtatttatc 3180

cctttacatt tacctgatta ttttatttta atattttatg tagactatga aaactgtgat 3240

agtcatcatt taaagttatt tccctgtcaa tgatttttat agcctatgaa gttcaggtgt 3300

ttacctaagt aagaacctca ggattaaata tatggttatt ttaccaataa ttccaagttt 3360

agctgttttc attaaaccaa caatatttga tatcttgttt gtcaaaaact acacaagcaa 3420

agatcattct gttttgggtt ggtgtattag tctgttctca cattgttatt aaaaaatcct 3480

ggaattgggt aatctataaa gaaaagaggt ttaattggct tacagtttta caggctatat 3540

aggaagcata gcagcttttg cttggaaact tataatcatg gtgaaaggtg aaggtgaagc 3600

aggcatgtct tacatggctg gagaaggagg aagagaaggt tgttggggag gtgccacaca 3660

cttttaaaca accagatctc atgagaactt actatcacca tgacagcccc aagggggatg 3720

gtgttaaacc atgagaaact accccatgat ccaatcacct tccaccaggt tcctcctcca 3780

acactgggga ttacaatttg acatgagatt tgggtgggga tacagatcca accataacgg 3840

ttgggtttac agttttataa actttatgtc aaattt 3876

<210> SEQ ID NO: 10

<211> LENGTH: 6995

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (3428)..(3428)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 10

tgtcttccta tccatcctac acatgtgcct atggccattg ggttgggagt ggaacacccc 60

caatattgta aaagaaaaga taggtgccat tacaatcccc ctaaaaagaa ggaaaatgcc 120

atagaaaaga ctgggttgga ctgaggccga tgttcctgac ccctgagagc aatggggggt 180

tgaagggtgg ggtgcaattt cccccatcct tagaaaacac ctgagaacaa gaaagctcag 240

aaacaaaagg gaaagaaatg ttctgggttc acattttact cacccaggca atgtcagctt 300

tctcattata acttttggct tttgattttt tttttttaat tttacaatct ggacaaatag 360

tgttttaaat acctttgttt taaccccctc aatttccatt ctatttattt catttcttaa 420

caaccatcca aagatttcta tcacccttct ggggcgactc ctttgactct cttttgcctt 480

tctcattttt ttttaaatta cctcaacatt ttattaagga tctgtaagac ccacaaggga 540

cagcaaattt gatacaactt gtcaaacaat tgtatggttc tgtcggagaa atgtcacctg 600

ggatgcctat gtaaaaggga cctctttaac ccccaaattt accatgacct gggtaatagg 660

catataaagt gggagaatat cctggtcatc ataaagccag taccatgtgg cttgcttatg 720

aatcatatct actgcttcat ctgggttact ccacttggca ttttataggg agagttgggc 780

agtccctttc ttggggtaaa cagactttac agtggcattt atccagtcca ctagggttgg 840

atgttctctc aggaataacc tcctatgcat ttggatcact tatactcatt agagatttaa 900

tagtgagctg tgggtcatgg atcaaactaa agaagctctt tcactctgta gcatttaaaa 960

ttaaggattc tatccttaaa ttagttattt ttaaatccat tatagtaaaa gtgtctcagg 1020

aagctgacta taccaatcta caaaatggaa caattccttt acattatagc ctctggtttt 1080

aatagttgtt ttgccctgcc cctacattta ctatcttctt ggtaaccaca ggtctcagag 1140

gtaaactttg ttgccccggt ttaatttata tttttgtgag tagcttggat gctagaggct 1200

tgagctgaga cagacccact tctggtcttg gtccactctt aaggaccaac ccaacactct 1260

tttactctca tttcagcttt tacagataat aaccaaagga tgaaacattt ttcttcctta 1320

ttagcttgcc ttcccttatg cattcaggga actaactccc tgggagtatg agtaggatcc 1380

atctctaatt ccactggtaa cttttacttt tagtaactga ctatagccca gctgcagctc 1440

cttaagatgg gcaaccacat ggctactcaa gagtcaggat ttctcatttc acaccctttt 1500

atttttttct ttatccattt agttttatct atataatttt ttcctttatt ttagagtgat 1560

tcataaatag tctctagaaa aaaattacat tttctttagc aaaaactagt tccttgtgtt 1620

ttcagaaacc tcaccaaaaa caccttttat tcacctacta gtttaagtct tattaactca 1680

aattcccagt ggaaaaaaaa ctcataggtt tacttaattt aaacattaca tgacttatta 1740

acccaaatcc ccagtggggg aaaaaagtaa cctaggttta cttaatttaa acataacatg 1800

actttaagat tttaaattac tggaaataat tgagattaaa tttaccaaat taatcttacc 1860

aaagattact agtcatgtga gctaaaaggc atctgagcta ggttccatca gtctgataag 1920

cattaacatt ctccaagcca attgattaga gctcttttgt accacttgtt agtgaaatat 1980

cacttccaca tggcacatgt aaacatgtag atataacaga catatagaaa acggcaggtc 2040

caaaagattt ttcatttgcc tcttttcaaa aattctctcc cctactttag attattaatt 2100

taaaaaagtt ataaggccaa acaaaagttg aaggagagag ttaccatcct aggccttttc 2160

aaaagcgaaa aaaggactga gatatcaatt tgaataattt caaaaagaaa cattacagaa 2220

tttaaaaatt aaaaactttg tgcattgagt aactcaatat tttaaataaa atcttgttct 2280

aaccaaatct ttagttattt attagtgtat ttttttttga gacagagtct tgctcttgtt 2340

gctcaggctg gagtgcaatg gtgcgatctc agctcactgc aacttctgcc tcccaggttc 2400

aagtgattct cctgcctcag cttcccaagt agctgggatt acaggcacct gccaccatgc 2460

ccagctaatt ttttaatttt tagtagagac agggtttcac catgttggcc aggctggtct 2520

cgaactcctg acctatatga tctgctcgcc tcggcctccc aaagtgctag gattacaggc 2580

gtgagcaccg cacccagtct agtgtatttt taacataaaa gttcaattta aaaaaaagat 2640

tataattttc tgtaattatg gacaacttaa tcacataaca tttgtataaa tttctttttt 2700

actaacttta ttatgactta cacagaccat tcacaacatg cttggacttt ctgctttgac 2760

ctaagtgtca ctctttctgg aataactcgg tcattttatc ttaggacaaa aattcaccaa 2820

acaatatttt tctcatacaa aattactttt cttttaagct ttcttaccaa aaatacctct 2880

gtatatctat acttttcttt atattggtct atttcctggt tcctttcaca ttcttattta 2940

tacaggactt ttaaataagc tttgaattag acaaaaatta tttacctttt aataagaaca 3000

tattttaaaa aaagaataaa atataatttt ttgaattgga aaatacccag atatttaatt 3060

aaatatctat tattgaattt aatataattt tatattctaa attatgacaa gtttatttac 3120

aggtatttat ccctttacat ttacctgatt attttatttt aatattttat gtagactatg 3180

aaaactgtga tagtcatcat ttaaagttat ttccctgtca atgattttta tagcctatga 3240

agttcaggtg tttacctaag taagaacctc aggattaaat atatggttat tttaccaata 3300

attccaagtt tagctgtttt cattaaacca acaatatttg atatcttgtt tgtcaaaaac 3360

tacacaagca aagatcattc tgttttgggt tggtgtatta gtctgttctc acattgttat 3420

taaaaaaycc tggaattggg taatctataa agaaaagagg tttaattggc ttacagtttt 3480

acaggctata taggaagcat agcagctttt gcttggaaac ttataatcat ggtgaaaggt 3540

gaaggtgaag caggcatgtc ttacatggct ggagaaggag gaagagaagg ttgttgggga 3600

ggtgccacac acttttaaac aaccagatct catgagaact tactatcacc atgacagccc 3660

caagggggat ggtgttaaac catgagaaac taccccatga tccaatcacc ttccaccagg 3720

ttcctcctcc aacactgggg attacaattt gacatgagat ttgggtgggg atacagatcc 3780

aaccataacg gttgggttta cagttttata aactttatgt caaattttga cacagagtat 3840

ttgtcaggga taagtatgaa attgctgatc aataaatgca aacaaaaata tatgttgaca 3900

atttataaga catttctaat attacttgac caataatttt aagccagttt atttataaaa 3960

ggttttactt gtcacatgac cttgaaaagc atttgggctt attgtttaat gtatgagtac 4020

ccttcaactt taagccattt tagtaccttg tggccaaaaa cacataataa aatacatgtt 4080

tgtacacata aacacacata tacacactca tacaaagatc ctgttgcttt cacttcaaaa 4140

ttttagctat gagatattaa tataaactta ccagtttgca aaaacaataa caaaaagaaa 4200

cggttggatg caaacagtgg attttatctc agtagaaatg tgttaataat agcagacaaa 4260

gcaggtggaa aagaaaacag agatagagaa cttaggaact ttagagttgc aggttgaact 4320

ttaggttctg aattttcctt gatgtaattt gcccatcagt ttaaaatgcg cacaagaaca 4380

gacctaatgt gtaaccagct ggagtattag aaaacctggc acgcccttcc atttacacaa 4440

ccacttgcaa gtagaggcac catgaaacga aatgaggtgc ctgagaggcc ttgttcttgt 4500

ttttccatat ccttaattta ttccccacat attttcttaa aaggaggaac tgagctgtgg 4560

cctaagtttt agtttagtgg gtcaaaatat gctgattctg ggtggggctc cacagtgtgt 4620

caccagtgag tcgttgccac cctcttatgt atctcagttt ctctctctgg aggtttagac 4680

ctccgagtgc tcaaaacatg gagttcctac atgagcttcc tggatgaacc tttttaaact 4740

aattttgctg ggggttccct gtagggcggc tgcatttcat ggggttggta gtcaacccct 4800

taggctccac cccagtaacc cagggatgcc ttttggctgg aaggagcaaa atgccctttc 4860

ttttcagagc ttaggaaact cagtctgaca tttatctaca aaaacaacag tttagttgct 4920

ctcacaaata cacagacaag ccaatcgaga ttaattttgg gagagaagac aatgagaaag 4980

ctctttagaa tgcacctctg aactagaatt aggatcctaa acaacaactt cattggtggg 5040

ggcagcgggg tggaaaaagc taagaccagc tgtaaactgt cctcagccac tcctaacttt 5100

atagctcttg tctgccatta cacactccaa ggtcacatct tctcacagta caaggtaatc 5160

tctggtgccc gcaaaagcca agagggtcag gtaatgcaat acaggaaagc agagttttaa 5220

atctaagaag aatctgccca tgactcttga aaccccacaa agaaaacaga acaccccaaa 5280

agggggtggg agtggtgcct ttgttctgag ttctttaagg ggtctgagac attagaaccc 5340

ttctgtagat ttttcttggt accagagatg gtgaaggggg aaggaaaaat agagtggaac 5400

aaaagtaaac agaagaataa ctgttttttg tttttttttt ttaagaaagg aagtgaacac 5460

agaaaccaag cacatgtttt tgtttttgtt tgtgcagctg ccaggaattt tagccaattc 5520

agaggccttg tttcccctaa tttggaattc tcattggaat ttgaccaagt ctgttatagt 5580

tgatcaaatc ctatgggaga aagatcagaa caacaaaaac cccaacaata tgattactga 5640

gtgctctaac ggtaaggaga aattaaaacc agctgcttgt caatttcaac ttgtagtcat 5700

taaggagaat ttccaagaca aaaaaatccc aattcttgct acttacctag gaatagagcc 5760

ctggcacaag attgctcttt accatcttag aagcaggaaa aatacctgga aaggtgcaca 5820

ggaacagaca taaggttctt gccttcccta tcggaaacta gctgaaactc cagaaatgag 5880

ttacctgcta tgcatcatca tggaagcaga aaaacttgct ttccttgttg gaatcaagta 5940

aaactccaga aaaggagttg tagagcaaaa taagctttag atctcgacca aattttgaga 6000

gatcagggat tctctggagg gggaactccc aggcctcagc aaattgtcct tctgatttga 6060

gccataagga tagctcaagc tggtaccaag caccaataga ttcatcaaag gtcaggggca 6120

cctccactca gaatcccttc atcaccaatt tgtgaactca aaagtatctg agacagatct 6180

caatacattt agacggttta ttttgccaag gttaaggatg tgcccatgac acatgtgccc 6240

atgacacagc ctcaggaggt cctgatgaca tgtgcccacg gtggtcaggg tacaacttgc 6300

ttttatactt tttagggagg cataatacat caatcaatac ctgtaagatg tacactggtt 6360

caatctggaa aagcaggaca acttgaagtg ggggcttcca ggttataggt agatttaaga 6420

attttctgat tggcaatttg ttgaaagagt tatgttgtta cccaaagacc cagaatcaat 6480

agaaatacct gggttatgat gataaggggt tgtagagacc aaagtttatc aggcagatga 6540

agcctccagg tagcagattt cagagagaat agattgaaaa tgtttcttat cagacgtaag 6600

tttaatgctg gtcagctttt cctaagttcc aaaagggagg agggtatact gagttatatc 6660

caactctccc ttcccatcat ggcctgaact agtttttcag gttaacttta caatgcgctt 6720

ggccaagagg gggcgtccgt ttagatggtt tgaggtgggg agggcttaca attttatttt 6780

tggcttacat agtaaaggtt aattatctca atacaattag gtcatcttca tttttctttt 6840

aaaaactttt gtcttccttt atctccctga atacacaggc agtttactat tttctcattg 6900

caagacccat tctcaaatat tattttcttt tagagagact cttgctgtta tttaggttca 6960

caagatggtg tcagaagtga aataaaagtg gcctc 6995

<210> SEQ ID NO: 11

<211> LENGTH: 601

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (301)..(301)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 11

tgaaatgctc tattctttgc ctcaagtgat cctcctacct cggcctccca aagtgctggg 60

attacaggca tggagccaac acacctggcc ttcacatcta tttttaatcc aagtaattct 120

agggtcaaat aatactgaaa tctcgctaag tatcaaacgc tgcttttaac tgaagaaagt 180

ttactttgtt ttattttatt tttaaaatct tgctttgtct ctagatagac accataaatc 240

agaacttctt aatctaagat aacatcctgc tgctcaaaaa caggtgtcag aggaggcaat 300

rcatgcagct ggctcattag tctatatcac agatgccaca aacatgctgt cttgaggaac 360

tagaaacgtg cttttttgaa atatgttctt cagaagttct taggagctgt ggtgggagag 420

cgcaagcctg ggggtgagga ggcagctgag tgggtgattc ttctcactat tgcatcaaca 480

agagtagtag ctatagactg ggtttcttat tcttctacta agaggccccg aaataaaatg 540

gctttttaaa ggacctggtc taaagctttt ttcttttctt ttcttttctg attttttttt 600

t 601

<210> SEQ ID NO: 12

<211> LENGTH: 2429

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (2000)..(2000)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 12

aaataaaaag atttgattaa attttttaaa tgggcaaagg atctcaatgg acaattctcc 60

aaggaaggta caaaatagcc aataagcata aaacagaagc tcaacatcat taattagcag 120

gtaaatgcaa ataaaaacca catgagttac cattttatac ctattaggat ggctatagtc 180

aaaaaagatt ggtaaaaatg tggaaaaatc aaaactctca tatattgctg atgggaatgt 240

aaaatagtgc agatgctttg aaagtagtct ggcatttcct caaatgatta aatatagagt 300

tactatgaga cccagcaatt ccactcctat gtatatattg aagagaaata taaaggtatg 360

cccagctatg tgtggtggcg tatgcctgat agtccttggt acttgggagg ctgaggtgga 420

aggattgctg gagcccaggg gttcaagact gaagtgagct atgtttgtgc cactgcgctc 480

cagcccaggt gacagagcag gatcctgtct ctcaaaaaaa caaacaagaa aaaaaaacaa 540

aaaaactcac actcaaaaat ttttacatga ctgtttatag tagcattatt cataatagcc 600

aaaaagtgga aactacccaa atgtctatca actgaagaaa ggataaataa tatgtggtat 660

atccatataa tgtattattt ggtcacaaaa aagaatgaag tactgataca tactacaatc 720

tgaatgaact ttgaaaacac gttaagtgaa agaagccagt caaaaaaatc atgtattata 780

ttagtctatc tagaacaggg aactctatag agacagaaag attagtagtt gccggggctg 840

agggctaagg gaatggtgag actggaaggt gatagccaaa gggtatggag ttgctttttg 900

aggtgataaa aatgttctaa aattgactgt gagtgatggt tgtacatatt tgtgaatata 960

gtaaaaacca ttaaactgta tgctatatgc ttaaagtata ggctgtgtga attatatctc 1020

aataaggctg tttaaaaaaa tctaagtgga tgcagtgacc atctatttcc ccagtgtcct 1080

gtagttgctc tatgggctct tgaacaaaat agttgcatga tggaggctat atatagactt 1140

aacaatatgg atctcctctt accaaagttg gtctgacctg cagagtgtcc aactttccag 1200

taaggaagat caatgttgaa cccctagtat agtgccatat tccaggggct ctcatcttcc 1260

atctcgttgc aggtaggttt atttttgttc ccttccaaaa gggagggggc aagagacatt 1320

ggttatagat tttctttact gctggatata gattctggtt acagattttg tttatagatt 1380

tttatttact gcttcaatgc ttttattagc agacccctaa ccactcctgg gaccacacat 1440

acacccatag atgtagtcaa tgccttgttc atgagcatag tactccacaa tacattgctt 1500

atgacaaaga acttaagtta atgtgaaagg agtgaagcaa ggtctcaaga cccataggac 1560

aaatatatat catatatttg tcgctcagaa atccatgact ttataggaag gtgaaatgga 1620

taattgaaaa ctcagtttga gagacgtctt gtgaattggc atatgaattg gtaaatgctc 1680

caattggtaa atgcttcact aagcctaggg ccaatatatg gtgctatttc ttccacagac 1740

agaattcact ggtctaggat acaagaagta gaagtgggag gggcaactct gactgttacc 1800

catagtgaac aacttatgac atgtttttgt ttcccatatg cttggccttg aattcttctg 1860

gtttataaca aaaatggttt ccaaaaattg gaagtcgagg ctctctcctg accatttgga 1920

gcgcctcatg ccatttaact aacaaaaaga aaatgaggtt cttatattgt ctagggtgat 1980

tcattctgat tttcaaggcr taatatagtt ataaatacaa tggggtcagg tggaagaatt 2040

cttggtatcc tctggtgtgc ctcttagagc ttctctattc agtgataaaa attaatgtaa 2100

ggttaggtca agcggagaca ggaaacacca aaaggactca aactcctcgt ggataaagag 2160

ctgaagtgct ggctggaaag aaagtgaatg ttgagtttat aatgaaggaa gaagtcataa 2220

atattaacta cagcttcatg actagttgac ttgttgcaat tatgaggact gtggtaaata 2280

tctttttttt ttcttgttct atttatgcac atctttatat ctatacatta aaccccttct 2340

ctctctctct ctactatttt atccaatgtc tgttggtaat ggttaatttt aacacctatg 2400

tcttagatta tattattcta tggttgtga 2429

<210> SEQ ID NO: 13

<211> LENGTH: 778

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (391)..(391)

<223> OTHER INFORMATION: m = a or c

<400> SEQENCE: 13

tcactgcctg atcagtcatc tttagaacat aaacattcca gaagttttca ggagatgaca 60

ggcacaattt cctgaaggcc tgcctagaat tgatttgcta acatgaagat agatggctta 120

atgcccttaa tctctctgtc tatggatttc ttctctcatt tttgtaacat cagtgctacc 180

accaccaaca gtaataacac tgcaccaggc actgagggac ttttatctgc attcactcat 240

ttaatttgcc cagctcttct gtgaggaagg tactgtgcat tatggtcttc ctcttacaga 300

ctgaaaaaac gaagccttgg acacctgaag gagattgcca ggcagccaat ggtgaagctg 360

attttgtacc cagacagtct gagtgcagag mctgccatta ccctccaaca gaaaaccaag 420

agcaaagcca tgggagagag gagctaatga aagaggcaga ccaattagaa gctgaggcta 480

tactttatct tcttccttct tccctcctcc tcctccttct ggccggcatt catcaaacat 540

tgaacatata tgaacattaa cttatgttag gcactatgtt caaagcttta caacttactt 600

aattcccaca gccaccaagt aaggtaaata tttttattat cgcattctac agatgaggaa 660

gctgaggctt tagaaagttg catctcttac tcgaggttac aggtttggta agatgcagag 720

ccaggaacat tttggtagca tttgaattcc tgccgtattt tgctaaatgt gcccttgc 778

<210> SEQ ID NO: 14

<211> LENGTH: 1001

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (501)..(501)

<223> OTHER INFORMATION: w = a or t

<400> SEQENCE: 14

ctaacattaa aaaggacatt gaaatagggg gctggaaaga taatgaatgg ccccctgggc 60

acaagatggg tcatggggat actgtactcc tatttatatg ttaaaccaca tcataaggtt 120

gcaagcagtt ctggaaatta tagtcaatga aacagcctga gccttagact tgctagccat 180

acaggcaacc cagatgagag atgccattta tcagaacagg ttagtactga attatgtttt 240

agcttcagaa gggggtttgt ggaaaactta atttaacaaa ttgctgctta caaattgatg 300

acaatggaaa agctgtcatg gaaatcactg ccaggatgcg gaagttagct catgttctgg 360

ttcagacatg gtctggttgg aacccgagtt cactctttgg aggacggttt tcatggtttg 420

gaggctttaa aactgtaata ctaggctttg tggccataaa aggtggatgc ctactgcttc 480

cctgtctctt gccatttcta wtcggaagca tccaatccac catagactca atggtagaca 540

gacataccac catccgaata aaggctctgc aaaagtacca actggtatcc caagatgagt 600

atgtacccac tcaagaagaa atagctaact gtggtgctct ttattaatct acatttgtgt 660

cgagcaccaa aagggggaaa tgaagaagga attaatgaaa tcaactataa cctaagagta 720

gtagtaatac aaattttaaa atccttttaa agttcctgca aaatgtgacc cctgccttac 780

attcacgtta aaagggaata ttaacagcct gtcttctctc tgtggacagt ggaccttatc 840

tatactcccc aactccacat tcctcaaagt ttattacagg cccagtgagt tcctgcatga 900

ctgcagggtc acaagactga taagtttagg ctgcaagaca tgtctttctc aaaatgtaac 960

aaacgttgta atactgcctt tgtttcttgc ttctgtaact c 1001

<210> SEQ ID NO: 15

<211> LENGTH: 7028

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (642)..(642)

<223> OTHER INFORMATION: k = g or t

<400> SEQENCE: 15

catatgaaca aaggtctgag ttgggtgagg caggatgcca cacagacatt ggaggaggaa 60

aatctgagca gggggcacag caaagcccca aggctgaggc cagatgaagg agcaggaggc 120

aatgtggctg gagaggaggg agcaaggggc agagtgttgg tggtgaggtc aggggcccag 180

cagcctgatc caggggactt gaacaggatg gaaggacttt gggtgcgttc tgaagaaggg 240

gaagccactg gaaggcatta agtagaaaaa attggaagtg agagtaatta tatgtgaaag 300

ttgttagagt cacaatggag tgacgatgag gcaggacagg tagtcaagga agtaagtgca 360

gttaacacaa tgagccccag tattcgcatt gtaatccagc tcatgcaagc acagctatct 420

cctgcaggga atatttccca tagacagcat ttgcactttg attttacctc ttctcaaacg 480

gaccctgttc tcatgataat agtaaaaaac acacccctag gtggagattt aagatgctga 540

tgaattatga gatgtatgaa caagcatgta cagctactgc acatgtgcac ccagaggacc 600

accgaggaca tgcttactag caacaccttt tctcaccctc tkatgaataa tcatgtaaga 660

gtcccataaa aggatttctc cagcaataat cagtgctgtc cattcagtgg ctcatgcctg 720

taacccagca ctttgggagg ccgaggtggg tggatcacct gaggtcagga gtttgagacc 780

agcctggtca acatggtgaa acctcgtttc tattaaaaat acaaaaaaag tagccaggtg 840

taatggcaca tgcctgtaat cccagctact tgggaggctg aagcaggaga actgattgaa 900

cctgggaggt ggaggttgca gtgagtcatg actgtgccac tgcactccag ccaacagagt 960

aagactctgt tccccctcgg ccccctgcaa aaaaaaataa taacaatgat aagaggcaag 1020

atcaatggcc accaaaattt tattttttcc catagcgttg ctggggtggc atggctgcct 1080

gccctgggtt catcctgtcc ctaagtggaa ctccctatgg ctgagggact cagaatcaaa 1140

tgacttatag ccaattaaat gttctagtcc agatgcccaa ttaaatgggc atggacagac 1200

attcattagc ctttaaatta ttttctaagt aaaaagtcaa caaacaaaaa gttaaaggtg 1260

aggttacaaa actgactttt ctttaacttc tatgctactg taatcttggg ttttgttatg 1320

gacttatagc aattatttat acaaaacata agaattgttc tgaaaaaatt aaaaaatata 1380

tacctgcatg gctcataact ggaaatatta taccaggagg ctttgtcact tggtatcttt 1440

atccttttac ttattatttt cttttaattc tacaggaagc agtaaattct ttatggttgg 1500

agtggatgaa gaggtgccat gtaatagctc agaaggcaaa gtcccttgtt ttaccagctg 1560

tttaggcatc catgtactca tccttgattt gaagggtttg agttaattct atccttccaa 1620

atcagccctt acaatctcac gtgcccacct cttctgcaac agtctctggg cctagaggga 1680

ggacgcttgc aatacaggat tttttgcatg ttcccagtgg ctccacccca ttctcccagt 1740

gcacatgcag gcccttagtc tgaacccacg ctacattgat ttatttccct tactgagcat 1800

gtgttaaggg atggaatttt tcaccatggg catgtttagg caagccccct gtacacaatg 1860

tcctggatgg catttggctg tcttctgcct ctatcattcc cccatctaaa agagtacatc 1920

taactgccat tagaataagg ataagaagaa agacaaagac ccatcttaac tgctttctgc 1980

tgacagaggg cactgttttg gaaagacagc agttgggtct ccctcagagg cctatctaag 2040

ggtatctggt aaaagggacc atcattcgag gctctggttg cataactgtt tggagtttga 2100

gggcctgaag gcgagaagag acaaaccagg ttattagaag acatgtacca aaatgaaatg 2160

ggggaagggt aaggacagtt caaaaatcct gaggctgctg acatgcccag ataactggta 2220

gctgtagttg tgcctgctaa gatttgggtg catgggactt ggctttggtt agctcccgta 2280

gtttattttc ccaaaaaaga aacctctggg ttatgggcac cctatttact cccattatct 2340

ggcaggattt gtaggataat tgttcagaac tagaatactg ttccagattt ttacattacc 2400

catgcctttt gtttcttctg agctgcagcc agagatcact ggttagttca caggaataag 2460

cagggttaat ttaaaatgta ggcaaaaaac ttaaaaacaa ctaatgagtc tagaatttaa 2520

tgacaaatgt atgataagtt ttgaaacata atttctttct ccccagtcct catttttgtt 2580

aaaaacaaat cataatagga gtgagttgtt tgtaaaataa actttagtct tacacttggt 2640

ctgcttattt gcacaaagta caacaagaat aattattttt acataggctt tttaaattgg 2700

ctttgatgga actctgttcc acaaggaatt tcagatagga cttcataaaa atgagcccag 2760

ccatgggttt gtaccctcta atacctatga gttgggtgaa ttgctctctt cttgaggtcc 2820

caagaatatg cggttcctgg ccctgttaga aagtgacatt ctttactcac tacaggttag 2880

ggaacctgta tggggactgt gtagacaaag tatgaggctg gtttacccaa ggggctttta 2940

ttggctctgc aagttgagct tgattcctta aagggaaaca tacccttcca gtcaaagtta 3000

cagttactgg ttggtaaagt taaagttaca gctactggtt gctaaagcaa ccagtttctc 3060

caattgcatc ctgttgcaaa agaaagtgga ttcttactgc actgatgcaa ataaccgtat 3120

tgccctaagt taagaatact cacagatagt ttccaaattc tagaggaagc aggcagagag 3180

aaaaaaaagt gctaaatttt gttcatagga gtctgcatta ctcaattatt aaagattgtg 3240

tatagctcaa aaaaaaagat cagcactgtt ttaagctaaa gtttaaaaaa gattacttca 3300

attttctatt agttcagtct gttcagttaa ctcttgttct gcttgatatt tgtgaacatt 3360

tcagctcttc atgagtcctg tacgtttttc cattattcca atgtcacaat ctccaaagtt 3420

atcagaaacc tgcatttgag agcacctgtt acgtttctat agctgattat aaatcctatt 3480

tgaagaagat caaaacaaaa caatggtctg tgaatagcaa aatgtccatg gtagttacag 3540

tcaaaaacac aattgacaaa gaaattttgt tatctctgtg gcttataatc acctaacata 3600

acacctttaa ttgtgagtga tagcatatac ttagatatta gaattttaga aatcccatac 3660

agttttggag catatattat tattcactaa aatataaccc aaagaagatt aaatatcatt 3720

ttggcaatcc catgtacata aatttgtcag gtaatcctat ttacctctct tctggatgct 3780

ccagggatgc taggggtcag gaaagacaac cttgaagctg acatttgatt ttgggaagcc 3840

cattaaatat gttagaggtt taaaacaatg ttatgaagta gaattccaga ttaccataaa 3900

ttacttattt tgccaaaatg atgactcaaa aattttaaaa caagccaaaa acttttactc 3960

atttagaggg aagacttaga tttccaaaga atttgtctcc tgtcttcact ttcatttcct 4020

tggcagtcta tctggaagac aaactgaaat atttaattat cctttactat tacatgaaaa 4080

tcttatacaa gggagagaaa gccaaatttt accctcacat tagtttacta ttaatgtcaa 4140

ccccaatttt ttaatgaaac cttatagaca attctatcca atcttaacca gtttgatcat 4200

gaggtaagat tcctgtaagc cttttataac cttttacaaa ttactaattt actaatctgc 4260

taaagagcag attagggctt taagaaaacc ttgttgtgct ttcatttcaa tgctcagttt 4320

gtagaaaaac catataatag agttttggat ttaatcaatg ttcacacaca gaatttcttt 4380

tgcaagatta atttttagaa acctcccaca acttgtttaa acctttagtt tatcttatct 4440

aatttataat agtcctttaa ccttaggcaa aaacttacat ttccatgcat tcttataatc 4500

tttgactaat aacacatttt actgttctta cataccttgc atgtaaatct attttcagtg 4560

gtctcaatta catgttataa tggtacctct tagcactttt taattttagt ttaaaacctg 4620

gtaagtcgtt ttaattacgc actaggtgct gataaagttt gattccttcc agcataatta 4680

agggtgtggt taattccata tgtccctgtg ccttaccaag ttgtaaagca ggcagattga 4740

acagttttca aaggcaaaag aagccgttta caaccttaaa acatttagcc acctagtgcc 4800

tgacttgcat aatttagacc agctatttac attttaagaa catttgcatt ttatcaatta 4860

tctttaagac tacttttatt tctcagagat taaagtcaca agaactaaaa ggcattatag 4920

cttttatctt tcctccaaaa atatttgatc ttagtgctga tttttcttta agccaattaa 4980

ttagagctct tttttataac tacacagatg gagaagaaga ttgagtgtta taagattttt 5040

catttgccca tctcctaatt ggattcttgg tctctgggtg ggacccttta agagcagggc 5100

taagaaagca tgcagtttat tttctttttt tctttttctt ttcttttttt ttgagaaaga 5160

gtttcactct tgttgcccag gctggagtgc aatggtgcga tctcagctca ctgcaacctc 5220

tgcctcccag gttcaagcga ttctcttacc tcagcctccc aagtggctgc atgcagtttc 5280

tagggcctaa taaacaggca tagctggaaa acaaaaacgg attttgagag cgatctattt 5340

gcctctaatt cctggggttc catgaggaaa acagaggttt ctcccaaaat ggaatccatg 5400

gtgccttttc tgtttttacc aagcagccct atgccatcag aaattatctt agggcctctc 5460

atgtgcgcat taacactggc aagacaaggt ggagaaaagt aattcagtca actgagaaaa 5520

aaatcttttt ccagcaaaac aagatccaag aagagaaaaa cataaaggcc tttcaaatat 5580

acgtatagct tggatatcca cttttaatta agctgagctc tctttaagaa agtcctttta 5640

aatcccacat tacctgactt cagccatgcc aagcagccaa tatttctggc tttggaagtt 5700

tatcaaaaga acctcaaggt tcaaccaaca agcctcaatt aagacacgcg aagcacacca 5760

gattggctac accttaagac cagcctcata aaaccttttt cactaatgga aactttacag 5820

ggaatatcaa cagtgatcct tatcattctt ttcaccagtt tacacaggga gagagaggcc 5880

aaaagtctga ctggttaaaa aacttttatc cttttgctgg catgtcatgc ttctgggttc 5940

ccttcccctg agctcaattc taagccaacc agtttaaggt ttgggaaatt aacttttctc 6000

agtttggagg atgcatccta tgggaatgtc ctttagtaca gggacacagt cacccatctg 6060

tgaagagagg acaaaggagg aaaaagtaaa aaaagatttt tttcaaaggc tccccagggg 6120

ttcaggatgc atttgaaagg gggacagatt gaagatgaat ggctactcat ctagaaagag 6180

gggagccaga catccctggt tcctttctct ttctaggaaa tagccagggt atgtgaggga 6240

aagaaggaac aagcatccat tttccttctt ccgtccttat gtccccaagt cctgacaacc 6300

tcgacagggt gccacccatg ggtgccaata cggttctcac ccatggtaac aggggaccta 6360

gtggatggga ttatccactg ttacccacaa actgtctttc cccctgctct caatagcctt 6420

caagtgccct agacctcatt taggccattg atactagtat gacctttatc catgaaacaa 6480

gaggcttggc ttaattgtca ggaattagtc atgctcacct atactgtgct ttttaatttt 6540

tgttgttgtc tgcctctgga tccctccgat gcagttatct ttcctagggc ttctacatga 6600

agcttggaat tgagtttggg acaaaagaac tgcctcagta ggtgggtgca tggactcatc 6660

aatccccagg tgtccctcac cagtctggct gctgccgcct tatcataagc tgaaggctaa 6720

ggtgcaactg tgaaattagg tccttctcaa acaagggagg gaaaatggtg tcctgtgaat 6780

tagggtcctg gtctaataag atgccttcca aaaggaagaa aacttctggc acagagaaga 6840

cccctctacc cgcagggctg tgttattagg ttggtgcgaa agcaattgtg gtgcccatca 6900

ttctaagtaa tgacaaaaac cacaactact ttcacaccag cctactaact catgacttgg 6960

tggacaaaag aaaataacaa caacaacaac agcttaaatg cagggctgtg tttactgctg 7020

acaaggtg 7028

<210> SEQ ID NO: 16

<211> LENGTH: 1656

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1001)..(1001)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 16

gggtatatac ccaaaggaaa taaagtcatt acctcgtgaa gatatctgta ttcctatgtt 60

aactgcagca ttattgacaa tagccaagat atggaaacaa actagatgtc cttcaatgga 120

taaactatga tatgtacata caatggaata ttattcagcc tttaaaaaga ggaaaatgag 180

gaaatcttgc tattttccac aacatggatt gacctggagg acattatact aggagaaata 240

agccagagac aaaaagaaaa atattgtata atttcactta tatgtggtat tcttcccaaa 300

agatcaaata tatagagaga atgaaacagg gttaccagtg ctggagtctg ggaggggaga 360

atggggagat ctaggtaaaa ggttacaaag tagcaaatat atagaataaa caagtcaaaa 420

aatgtgttgt acagcaacat gtggattaaa attaataata gtgttatata caggattttt 480

tctaaactaa gtatattata gctgtttgcc acaaggagaa acatggtata ttagctcatt 540

ttgcattgct gtaaaggaat acctgagatt aggtaattta taaagaaaag agattgattt 600

ggctcaccgt tctacaaacc gtacaagagg ctcatggttc cacaaaccgt gcagcttctg 660

cttctggtga agacttcagg aagctttcaa tcatggtgga aggtgaaggg aagcaggtgt 720

gtcgcatggt gaagggaagc aggtgtgttg catgatgaag gtgggagcga gggcaagggg 780

tgaggtccca ggatgtttaa gaaccagctt tcatgtgaac aaacagagca agaacccatt 840

cattactgca aagagggcag caagccattc atgaaacatc cacccccagg actcaaacac 900

ctcccaccaa gcctcacctc cagcactggg gatcacattt caacatgagg tttggagggg 960

acaaactata tcaaatggta actgagaaga ttaataaatt rttccactat agtaaccatt 1020

ttactacaca catgcatctt ataacatcac gttttatacc ttaaatatac acaatacaat 1080

ttttttttaa aaaagctagt tagatatgga atttaccaat gagtgaatgt tttccagtaa 1140

ttgtgtagac ttcagagctc tttctggcga gtacatatgg cctccaactt aataaggttc 1200

gacttaaggt tttttgactt acgatggatt catcaggatg taacctcaca ataagctgag 1260

gagcatccat atgtacctcc attcatgctg gataaatgga ttcttttttt tttttttttt 1320

tttttttttg agacacagtc ttgctctgtc actaggctgg agtgcagtgg catgatcttg 1380

gctcattgca gcctccgcct cccggattca agcaattctc ctgcctcagc ctcccgagca 1440

gctgggatta gaggtgcatg ccaccacacc agctaatttt tgtattttta gtagagacgg 1500

ggttttgcca cgttggcccg gatggtctca atctcttgac ctcgtgatcc gcccgcctcg 1560

gcctcccaaa gtgctgagat tacaggcatg agccaccgcg cctggccaac aaataggctc 1620

tttaaggcac tgctcttctt tgtccctgag agcaga 1656

<210> SEQ ID NO: 17

<211> LENGTH: 936

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (436)..(436)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 17

tgagtgtcac ttcctaggta ttgtttcttc tccctggctg gtggtcaagt ccagaagtcc 60

tgtcccagaa tttcttcaaa aggagagagg gagtaaaatt gggtatggaa aaaagactca 120

cattgacaaa aaagaatttt agagtcttct ctaaaatgtt gcggcaagta gataaaacca 180

tgaaaaacca ggatgcccta tgtgattgtt aatattaagt gtcaacttga ttggattgaa 240

ggatgcaaag tattattcct gaatgtgtct atgaggatgt tgccaataga gattaatatt 300

tgagtcagtg actgggagag gcagacccac cctctatctc agtgggcacc atctgagcag 360

ctgccagcgc agctagagta aagcaggtag aagaagatgg aaagaacaga cctgccgagt 420

cttctggcct ccaccyttct cccttgctgg atgcttcctg ccctcgaata tcagactcca 480

agttcttcag cttttggact cctgcactta catcagtggc ttaccagggg ttctcaggcc 540

ttcagccaca gactgaaggc tgcactgtca ctttcgaggt tttgagactc ggactggctt 600

ccctgctcct cagtttgcac acggcctatt gtgggacttc actttgtgat tgtgtgagtc 660

aatactcctt aataaactcc ctttcatata tacatctatc ctattagtcc tgtccctcag 720

gaaaccctga ctaatacacc ctataggcag atgagcctat tttacctggg gttagatcaa 780

agttgtttga gggaaggggc aacagaagag agctaacttc tcatgtgcca atgagaccga 840

aggaaagatt ctaatggaca cacaagatgc aatacagaaa tctggagaaa tggttcaata 900

gggaacacac agctcctagt gaggattaag cacccc 936

<210> SEQ ID NO: 18

<211> LENGTH: 938

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (363)..(363)

<223> OTHER INFORMATION: s = c or g

<400> SEQENCE: 18

tgggggtgct taatcctcac taggagctgt gtgttcccta ttgaaccatt tctccagatt 60

tctgtattgc atcttgtgtg tccattagaa tctttccttc ggtctcattg gcacatgaga 120

agttagctct cttctgttgc cccttccctc aaacaacttt gatctaaccc caggtaaaat 180

aggctcatct gcctataggg tgtattagtc agggtttcct gagggacagg actaatagga 240

tagatgtata tatgaaaggg agtttattaa ggagtattga ctcacacaat cacaaagtga 300

agtcccacaa taggccgtgt gcaaactgag gagcagggaa gccagtccga gtctcaaaac 360

ctsgaaagtg acagtgcagc cttcagtctg tggctgaagg cctgagaacc cctggtaagc 420

cactgatgta agtgcaggag tccaaaagct gaagaacttg gagtctgata ttcgagggca 480

ggaagcatcc agcaagggag aaaggtggag gccagaagac tcggcaggtc tgttctttcc 540

atcttcttct acctgcttta ctctagctgc gctggcagct gctcagatgg tgcccactga 600

gatagagggt gggtctgcct ctcccagtca ctgactcaaa tattaatctc tattggcaac 660

atcctcatag acacattcag gaataatact ttgcatcctt caatccaatc aagttgacac 720

ttaatattaa caatcacata gggcatcctg gtttttcatg gttttatcta cttgccgcaa 780

cattttagag aagactctaa aattcttttt tgtcaatgtg agtctttttt ccatacccaa 840

ttttactccc tctctccttt tgaagaaatt ctgggacagg acttctggac ttgaccacca 900

gccagggaga agaaacaata cctaggaagt gacactca 938

<210> SEQ ID NO: 19

<211> LENGTH: 1239

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (458)..(458)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 19

tctctgctgt ggcaccagga ctgcacgaga tctggtctct gcacatcttg gtgtctgcat 60

cctggtaaaa aatggccccc tttcccacac ctacccatgg aggaagatga ggcagcaagt 120

tgtaagaaat taccagaaaa gcctcactcc tgatctcctg acccaccccc tcatgctctc 180

agtgcttcta ctcttgcttc attaatttat ccaacaaata ctaattgtcg gctaggtacc 240

aagttctgtt atagataatg aagatatggc tgtggaaaaa gaaccagaaa cctgccttta 300

cattctagtg gaagaggagg aagataaaca ataaacaagg tcaacaagta actacagcat 360

gtcaggtgat ttaagtgctg ggaaggaaac tgagtggtat agatcattgc agagggtagg 420

ttgcaatttt aaatggaata gtgaagttag cctcactrat aaggcagtct tccagcaaag 480

atctgacaga ggtgaggaag tgaatctatg gaaacctggg ggtacagcct tccagcaaat 540

aacaggtgca aaggcccaga agcctagggc atttgtattt gagggcaagc aaggggtctg 600

tgtgctggag aagagtgagg aaggtgagaa ttagggagtg aggcctggga gattatgagg 660

aaaggaaaca gatcatacag cgccttggag gccattataa agactttggt ttttaccctt 720

atgagatggg aagctattgg cggttttaga gcaggaaagt gacatgatct gatttatgtt 780

ccaaggctca tgctggccac cttgttaaga caaaactgga gggaggcaag cagagcgggg 840

acaccaatga ggtaaccata gtgaccatcc agaggagaaa tgatggtggc ctggaatagg 900

tagttctgag aagtgttgta ttttggaggt agatcaatag aatttattgg tgcattgaat 960

atatatgatg tgaaagaaag cggggagaca aagataacct caacgctttt ggcctgagca 1020

gctgtaagac tgggattgca tttgatcaca gggcaagctc agtcgggctc aaaactgttt 1080

gctccttcct ggctggaact tcgtgtgggc ctaagatgtt taactggaat ttcatctggc 1140

agacttaaac attgtgttct tcttttaaaa gctcaaataa caaatattcc aaaatgtaaa 1200

gcaaaaaaag gatttattga aatcatgtga caatatatc 1239

<210> SEQ ID NO: 20

<211> LENGTH: 801

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (401)..(401)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 20

aaatatttaa taataataaa tatataaaaa gtatattcat ataaaataga aatgtatgaa 60

aaatattcac ctttatagaa gttttaaatt gtcaaagcaa tgtcaattta attggctcaa 120

taagagagtg aaaaaccatt gcttcaggac cgcctcagtc tgtaatgcta ttttaaaaaa 180

attatttcaa cattttctta aatactattc cttggttgtt aaatttttat tttgctgtat 240

tagaagaatg aaggttgtta ttagggatgt tacattcaga aataaagttc tgaatttcat 300

agaacacttt attctctgcc tcatctttac atttcaattt ttcgggggga atgtcgttca 360

aatatagttt acaaatgaaa tataaaggat aaaagaatgg rtaaacaaag aagtccccaa 420

ggtgtaacag tgaatattgc tttaagaaaa tacaaaaaca attttaaata agatccttca 480

aacacgagtc atcctgttct cagggagctt tagaatttcc acattgctga atgccaaatt 540

ccacaagtca tggaatttcc acacatctct cttcacttct ctgacttctt ctgtctaaca 600

tgggctgata tatttcagcc actacacagt agctggagtg tggtgttaga gcttcaattt 660

caaccgctct gtgagcccct tcataaacct tttgctccta cacacgagag agaaaataat 720

cagttggtaa atggctgcca ttaagtcaca gctgcatttt tgtttaaatt aacaagttgt 780

acatggtcac agcagtagat g 801

<210> SEQ ID NO: 21

<211> LENGTH: 1715

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (219)..(219)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 21

tcctatatag agatgaggaa ggcgccacaa gcaagacact cttggccaga aggattgagt 60

aatgaggttt cctttcttct ttgtcactaa aaaaattaca tttaattttg agaataaaga 120

taagttcttc taagacagga ttaaaaacta aacaaaacaa aaacaaacag aaaagaaaag 180

cttaatatat cttttaaatg agggacaatt gtacagagya gacttccttg ttgttgatag 240

ttttaattca gatatcaatc cagaaatcat aagatttttt tccccaaaac ctgttcttat 300

ttacataaag tagactttaa aacaaaattt tgattcatta agtagaaata tttaataata 360

ataaatatat aaaaagtata ttcatataaa atagaaatgt atgaaaaata ttcaccttta 420

tagaagtttt aaattgtcaa agcaatgtca atttaattgg ctcaataaga gagtgaaaaa 480

ccattgcttc aggaccgcct cagtctgtaa tgctatttta aaaaaattat ttcaacattt 540

tcttaaatac tattccttgg ttgttaaatt tttattttgc tgtattagaa gaatgaaggt 600

tgttattagg gatgttacat tcagaaataa agttctgaat ttcatagaac actttattct 660

ctgcctcatc tttacatttc aatttttcgg ggggaatgtc gttcaaatat agtttacaaa 720

tgaaatataa aggataaaag aatggataaa caaagaagtc cccaaggtgt aacagtgaat 780

attgctttaa gaaaatacaa aaacaatttt aaataagatc cttcaaacac gagtcatcct 840

gttctcaggg agctttagaa tttccacatt gctgaatgcc aaattccaca agtcatggaa 900

tttccacaca tctctcttca cttctctgac ttcttctgtc taacatgggc tgatatattt 960

cagccactac acagtagctg gagtgtggtg ttagagcttc aatttcaacc gctctgtgag 1020

ccccttcata aaccttttgc tcctacacac gagagagaaa ataatcagtt ggtaaatggc 1080

tgccattaag tcacagctgc atttttgttt aaattaacaa gttgtacatg gtcacagcag 1140

tagatgggtt gtggggtttc ttcccagaca catccttctt ttctagagtc ctaggccata 1200

gcctggtaaa gggacaaggc aagtggctgt gtaggtgcaa cttgacttct ccttgagggc 1260

tgttggctgg ttgaccccat ggtcagagtc ttgtttttaa gaattttgtt tgttttttga 1320

gatacagttt cactccatca tccagcctgg agtgcagtgt caccatctcg gctcactgca 1380

acctctgcct ctcaggttca agagattctc gtgcctcagc ctcctgagta gctgggattg 1440

cagacgcata ccaccacgcc tggctaattt ttgtattttc agtagagatg gagtttcacc 1500

atgttgacca ggcaggtctt gaactcctga cctcaaatga tttgcctgcc tcagcctccc 1560

aaagtgctgg gattacaggc atgaaccacc ccacctggcc ttctttttaa gaatttgaag 1620

tgtgcagtga gaatgatgtg cagcgagatg agcagagata actgcaggca tgaaactgtg 1680

gccacataga gacagaaagt ctgagagaca gagca 1715

<210> SEQ ID NO: 22

<211> LENGTH: 1231

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (201)..(201)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 22

agctgcggac atcacagggc tcctggctta tgatctgtga tgctagattt tgcaattgat 60

tgcaaaatca gttttgcaat cagttgcaag tttcttgacc cattcactgg attgtgattg 120

tgttacaaga ccaagtcaag attatttgac ctcatagcac tttactcttt aacagctctc 180

tccttgaaat attaccttcc ygcactattc atgaacatat cagcccacag atttcctcct 240

acctctttgg ctattccttc tcagtctcct tttaagattt ttcttactca ggcatctttg 300

ggtgaaagtc cctcaatatc tggtcttact caaaactgcc tctcactcac tactctctcc 360

ctaggcaatc ctatcaatgt ccactgtact gtatgcatga aatgactcac aaatttttgt 420

ctctaataaa gactttactt tgagtcttgg atctgaagag atatgtcccc tggatctctt 480

aaaagcatat taagcttaac atattcaaaa ccaaactcat aatctctatt accttgcatc 540

ccaccaaact ggtctttttc atcaaacccc atcaaaaaga tctcagcaat tcatctaatt 600

atgcatgcaa gaaacttaga ggtcatcttt gacatgtcct cttcaccatt atatccgatc 660

tatcacctgg tcctgccaat gttgcttact aaatgtccct ccaggaataa attttctcta 720

gtccttttca taagccaaat tcggtctcct gtagactatt attagtaacc tgctacttca 780

cttatctgca tccaacctgt tccccaaaat atagtcaaaa tgatcttttc tatacacaag 840

tctgatcata tggctcctaa ataaaattat gtttttctgg aggaagtcac aactccttaa 900

aaaattcttg tacctgccta cctttccagt cccatctcat tatggactcc ttcctgcatg 960

ctcttcttca atatattggt tatctttcag tcccttgagt ttgctatgcc agagggcctt 1020

tgcaaatgct ggtcccttgc ttgaaatgct ctattctttg cctcaagtga tcctcctacc 1080

tcggcctccc aaagtgctgg gattacaggc atggagccaa cacacctggc cttcacatct 1140

atttttaatc caagtaattc tagggtcaaa taatactgaa atctcgctaa gtatcaaacg 1200

ctgcttttaa ctgaagaaag tttactttgt t 1231

<210> SEQ ID NO: 23

<211> LENGTH: 511

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (256)..(256)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 23

tttcaacatg aattttggtg gagacaaact caaaccatag cagcttggga gtcctcttta 60

ggaaaagatt tataaatata aaatccttgc attggggtcc tgaagtttaa tcttcattag 120

attcatggta aaacagtttc taatcttctt agtactttgg accacaaata ggtccacttt 180

tgacctattt atactactcc aggggaagca taaaaagagt accaatcttt actttctgca 240

tgctgaaagt atctcyagca atgcacaaat ctacttttgt aatggagaaa ccttcattgt 300

aaagatttgt acattttaca atcgctacat aaaatatgta gagagaagtc gtagcggtta 360

aagatggaga tgcttctggg gatattcctt ccgaaattaa ttagcaggaa aatctgacct 420

aggacctacc ccatgctgga gagacatgga tgaatttatg ggataaaaat tgctactttg 480

gccatagctg catttgattt cctgaatttc t 511

<210> SEQ ID NO: 24

<211> LENGTH: 701

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (201)..(201)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 24

tcatgctaat gaggaaaact gcccaagacc ctgctggggg gtagtgtttc tgagactaat 60

catggcatgg catgggataa ttttgcactg gcatgacttg tgctttcttc ctcaaatcag 120

gcaacatagg tggtacaacc ttgcttgcct ttagttgcat ggaggcaaga gaattttggc 180

aaaattttac ttagggttca rggtttttta taagggataa gaagttgggc agaaggagga 240

gtcaagaagc atatcttttt tttttggatg gagtttcact cttgtcgccc tggctggagt 300

gcagtggcgt gatctcagct cactgcaacc tctgcctccc ggattcaagc gattctcctg 360

cctcagcctc ctgagtagct gggattacag gtgcccgcca ccatgcctgg ctaatttttt 420

tgtattttta gtagagatgg ggttttgcca tgttgggcag gctggtctcg aactcctgac 480

ctcaagtgat ccgcccacct cggcctccca aagtgctggg attacaggcg tgagccactg 540

cacccggcca ggaagcatat cttctgtttt ctccctgacc tcatcttctg tcaccccgac 600

ccctgtgttt gcagtgttga ctccttcact tgctccacca tgactccagt gactctgcct 660

tagggcctct gcactggccc ttcccttttc ctggtctgct c 701

<210> SEQ ID NO: 25

<211> LENGTH: 801

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (401)..(401)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 25

ttgttctgta tgaagtctct gcaccctcta gagagccttt tctttagtgg gaactcatta 60

agtacatgtg gggtcattca agctgcagat agacactaac cccatgcctg ctctgatcat 120

ttagtgacat caaaagctgc agcctttata aagttcaaaa aagcaccagt gccatttcca 180

acagatcctt gattggactc agatgacaaa gctatgagca attaaaaaga aacaaagcac 240

ttacctgcta caccagtaag gaagaaactg atgaggaagc ctagaaagca atgtttaggc 300

atcatggttg caagtgtgac tgttcaggca accagtgttc cttttaacca gctcaggacc 360

aaagaggaaa ctgtaaaatc cacaaacaga caatcactcc ygggtttaag gcagatggtt 420

ccttgaagca actacaattt tattttgata ctacattata ttattttatt ttaggaaaaa 480

tatgaaagta taaaaatcac ttcaaaaaac atttgctgtc acttttatgt ggaagctcgt 540

tttattggga agctcgtttt ttgttggggc ttcattagct gcagaaaggt aaaacactga 600

ggatgggcag atctgaaggg cagggcagtg cagggattgt gcaagtggca agcaggtgag 660

tgaatgaaac aactagtggg gccttaaggg aatctggccc caggaggcgg agaggctgcc 720

aaggactagg acttggctgc cagggtgatt ttgagtaatg tgcttggcat ttgcagctat 780

cggggcccct ggcagtggtt c 801

<210> SEQ ID NO: 26

<211> LENGTH: 2172

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (2033)..(2033)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 26

tgcctgatca gtcatcttta gaacataaac attccagaag ttttcaggag atgacaggca 60

caatttcctg aaggcctgcc tagaattgat ttgctaacat gaagatagat ggcttaatgc 120

ccttaatctc tctgtctatg gatttcttct ctcatttttg taacatcagt gctaccacca 180

ccaacagtaa taacactgca ccaggcactg agggactttt atctgcattc actcatttaa 240

tttgcccagc tcttctgtga ggaaggtact gtgcattatg gtcttcctct tacagactga 300

aaaaacgaag ccttggacac ctgaaggaga ttgccaggca gccaatggtg aagctgattt 360

tgtacccaga cagtctgagt gcagagcctg ccattaccct ccaacagaaa accaagagca 420

aagccatggg agagaggagc taatgaaaga ggcagaccaa ttagaagctg aggctatact 480

ttatcttctt ccttcttccc tcctcctcct ccttctggcc ggcattcatc aaacattgaa 540

catatatgaa cattaactta tgttaggcac tatgttcaaa gctttacaac ttacttaatt 600

cccacagcca ccaagtaagg taaatatttt tattatcgca ttctacagat gaggaagctg 660

aggctttaga aagttgcatc tcttactcga ggttacaggt ttggtaagat gcagagccag 720

gaacattttg gtagcatttg aattcctgcc gtattttgct aaatgtgccc ttgctgttac 780

caagtaccag agtcttctca aatccaaaca cttctggaag atgaaggctt gaattgcttt 840

tatgtattag tcactggaca actgcaccat cttggcaagt tacttaaatc acttacactg 900

agaggtaccc atttgttaac ttgcattctt acaggcttgc tcagaagtat gtggtgctga 960

taagatgctc tacactcctg cagtttcctc cacgaatacc agaagcaaat tctcacctgt 1020

tgtttgtggt ccctatcctg tgccaggcac ttctctaagc atttggcata tattaattga 1080

tttaatcttc acagtgacct agaatcccca ttctactaat gaggaaattg agggtgttaa 1140

gtaaatttcc caagttttcc tagatggtaa atggcagatc tgaaatccag accatgatag 1200

cttggcttag gagcctgtgc tggtaaccac catgatttag tgttccttca aggtaaaaga 1260

cattctaagg tgagtgagag ccagagagaa agagagaggg agagaaagaa agagggaggg 1320

agggaaggag agagagagag agaaatggat gtacatttgt tctgtatgaa gtctctgcac 1380

cctctagaga gccttttctt tagtgggaac tcattaagta catgtggggt cattcaagct 1440

gcagatagac actaacccca tgcctgctct gatcatttag tgacatcaaa agctgcagcc 1500

tttataaagt tcaaaaaagc accagtgcca tttccaacag atccttgatt ggactcagat 1560

gacaaagcta tgagcaatta aaaagaaaca aagcacttac ctgctacacc agtaaggaag 1620

aaactgatga ggaagcctag aaagcaatgt ttaggcatca tggttgcaag tgtgactgtt 1680

caggcaacca gtgttccttt taaccagctc aggaccaaag aggaaactgt aaaatccaca 1740

aacagacaat cactcccggg tttaaggcag atggttcctt gaagcaacta caattttatt 1800

ttgatactac attatattat tttattttag gaaaaatatg aaagtataaa aatcacttca 1860

aaaaacattt gctgtcactt ttatgtggaa gctcgtttta ttgggaagct cgttttttgt 1920

tggggcttca ttagctgcag aaaggtaaaa cactgaggat gggcagatct gaagggcagg 1980

gcagtgcagg gattgtgcaa gtggcaagca ggtgagtgaa tgaaacaact agyggggcct 2040

taagggaatc tggccccagg aggcggagag gctgccaagg actaggactt ggctgccagg 2100

gtgattttga gtaatgtgct tggcatttgc agctatcggg gcccctggca gtggttcaaa 2160

gcaagagggg tc 2172

<210> SEQ ID NO: 27

<211> LENGTH: 3078

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1078)..(1078)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 27

aaaaaagtca tgttccatag tgaacaggtc tgtgcaaacc tacccttaaa gtccaaggaa 60

gctgagaggt caaagaaaaa ggctgacata tccagtttct cagaaagaaa catttcgtag 120

ggacttatga acagagccat gtgtgtgtcc tggacagtgg caagacaaga tggtggaccc 180

tcatgccatt accctgtaga cctgaagaag gaattaagga aatcaactat aacctaatag 240

tagtagtagt aatagaaatt ttaaaatcct cttaaagttg ctgcaaagtg tgacccccca 300

ccttacactc aagttaaaag ggaatattaa cagcctgtct tctctctgtg gacagtggac 360

cttatctata cttcccaaat ccacattcct cagagtttat tacaggccca gtgagttcct 420

gcatgactgc agggtcacaa gactgataag tttaggttgc aagacatgtc tttctcaaaa 480

tataacaaat gttgtaatgc tgcctttgtt tcttgcttct gtatctcgct tcctgcctca 540

tgtagttccc accttaagat gtttaaacgt aggaaaagcc ctttgctcag ggctcagact 600

ttctggacat atgtgctact gatcacctta atttagtaaa ctctcctgaa cctttttcgg 660

tctctccaat ctttggttgt cccacaacat ttccggggac cagtctggga ttggagatgg 720

cagattttcg tctcctttgc ctgtgggtta gagccccagg acatgggaaa tctggggtcc 780

ttggtgccac cgggagagtt ttagcccaga aggagaacag cccttccacg ttctggagcc 840

ttcctccaac agtgcaaatg gaaccagtgg aaagggttgc aggacagtca caagaacagt 900

gcatagacat atgaactgca gtaaggtttg ggccctaagg caagacccgt cccataagga 960

tggaagggga gcctggtcac ctccaagggc atgacaacta gtctgacccg agggggttgg 1020

gacaatggga gaggcccatt gattcagatg aaactcacac cctaattgac accagacrta 1080

agtggggctc atgagtcggt cagaaaggaa aaccattttg gggatggggg aggtgtgtga 1140

aagtgtgtaa aagagatggt ctcgggagag accaaggcgg ggttgatgtg gggaggcaca 1200

gatctcttag cgtggactgt gtgctcccag gcgagtgtgg gaaaaaccag acctaggaca 1260

ctgcatacgg cccagaggac cagctccaca gctgcagcta gctgtgacag gaattaaggc 1320

atgctcctgg ctaagcagtg tccgaacctc ctgtaatagg acccagtctg gtggatccaa 1380

gagtgaaagt gagagtgaaa gtgcatcaca agggaggaaa caggaggaaa agcgtcaaag 1440

cctattccac tggagtgcgt gctgaaaaac tttaaaaaaa gttttaatgg tgactatggg 1500

gttaagctaa cttcacagaa actgagaact tttttgagat aaaatagcca tcttttaatg 1560

tagggtggcc agccaagggg acaatagaca gggagataat tggccgagtg tttcgggtgg 1620

tcaccaggct tggagaacag cccgggcacc tggatcagtt tccgtatatt gactcctggc 1680

taagtataat tcagaccctc cctaagtggc tgcaggccta ctttgagatc tactgtaaga 1740

ctctaacggc caagacaaaa ccaggaacaa tagaaagaaa ctgcaaggca tcagaaaaag 1800

aaaagtcaca ggaaaagcag taaaaacctg tcctacaggc cccgcctgaa gagttagaaa 1860

ttccacccca ctatgcacca atttatccac ctctggcaaa gcttagacag aaggctgccc 1920

cggctgcctc cggagactca gactcagaag gaagcacccc tcaggcaaca ccacgcagag 1980

aggagccaga gcccttgact gaaaagccaa gggaggaact ccagggtgat gaggtcggcc 2040

gccttaggtc ggtccgtgcc caagcaatgc agatgccact ctgagaaaca tggggacaaa 2100

tttatttgaa tgcacagaat gaagtccaag ggggagaaca gctcttcttt tatcagccct 2160

tctctactac tgatctctta aattggagac aacatactcc ctcctataga gagaagcctc 2220

aggctcttat agatctaatg cagtccattt tcctaactca caatcctacc tgggttgatt 2280

gtaaacattt ttttctgtca ttatttaata tggaagagca ccgtagagtt atacaagctg 2340

ctctccagtg gctggagaaa aatgcatctt caagcacagg agatatcagg cagtatacac 2400

aacaagcact cctgatagag gctgacccag gctgggaccc taaccaggct caagggctac 2460

aagtttgcag cagtattgag aggcactcct aaatggaata aacgctggag agaaaaaggc 2520

caccaatatc ggaaaggtct cagaggttcg ccagaagcca gataaaagtc ccggtgaatt 2580

ttatgagagg ctgtgcgagg cttaccagct ttacatgcca cttgacccag aggctgcggg 2640

taatcagtgt atggttaatg tggcatttgt aagccaggtg caagaagaca tcggaagtta 2700

gaagggtttg aaggtgtgaa tattacccag cttatccagg tggctactaa ggtgtttgta 2760

aatcagaagg aggaggccaa gagaaaagct agatgcagag ctaaggaaaa ggcagacttg 2820

ctggcggtgg ccttagttgg aagagaaact ggttttgtga gaggatgtgg tcgtggttgc 2880

ggtcatgata gaggacaaac taggtaaaac caggaagcta agccaggaca agagggccaa 2940

cttaggctta agggagatca atgtgtgaga tgcaagcaga tgggacacta gaagaatgaa 3000

tgccaaattt tccggtgccc ttgttaggaa gagatttcct ccagaaattg caagcacaaa 3060

tctcctttat accagaag 3078

<210> SEQ ID NO: 28

<211> LENGTH: 3164

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (1164)..(1164)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 28

aaaaaagtca tgttccatag tgaacaggtc tgtgcaaacc tacccttaaa gtccaaggaa 60

gctgagaggt caaagaaaaa ggctgacata tccagtttct cagaaagaaa catttcgtag 120

ggacttatga acagagccat gtgtgtgtcc tggacagtgg caagacaaga tggtggaccc 180

tcatgccatt accctgtaga cctgaagaag gaattaagga aatcaactat aacctaatag 240

tagtagtagt aatagaaatt ttaaaatcct cttaaagttg ctgcaaagtg tgacccccca 300

ccttacactc aagttaaaag ggaatattaa cagcctgtct tctctctgtg gacagtggac 360

cttatctata cttcccaaat ccacattcct cagagtttat tacaggccca gtgagttcct 420

gcatgactgc agggtcacaa gactgataag tttaggttgc aagacatgtc tttctcaaaa 480

tataacaaat gttgtaatgc tgcctttgtt tcttgcttct gtatctcgct tcctgcctca 540

tgtagttccc accttaagat gtttaaacgt aggaaaagcc ctttgctcag ggctcagact 600

ttctggacat atgtgctact gatcacctta atttagtaaa ctctcctgaa cctttttcgg 660

tctctccaat ctttggttgt cccacaacat ttccggggac cagtctggga ttggagatgg 720

cagattttcg tctcctttgc ctgtgggtta gagccccagg acatgggaaa tctggggtcc 780

ttggtgccac cgggagagtt ttagcccaga aggagaacag cccttccacg ttctggagcc 840

ttcctccaac agtgcaaatg gaaccagtgg aaagggttgc aggacagtca caagaacagt 900

gcatagacat atgaactgca gtaaggtttg ggccctaagg caagacccgt cccataagga 960

tggaagggga gcctggtcac ctccaagggc atgacaacta gtctgacccg agggggttgg 1020

gacaatggga gaggcccatt gattcagatg aaactcacac cctaattgac accagacgta 1080

agtggggctc atgagtcggt cagaaaggaa aaccattttg gggatggggg aggtgtgtga 1140

aagtgtgtaa aagagatggt ctcrggagag accaaggcgg ggttgatgtg gggaggcaca 1200

gatctcttag cgtggactgt gtgctcccag gcgagtgtgg gaaaaaccag acctaggaca 1260

ctgcatacgg cccagaggac cagctccaca gctgcagcta gctgtgacag gaattaaggc 1320

atgctcctgg ctaagcagtg tccgaacctc ctgtaatagg acccagtctg gtggatccaa 1380

gagtgaaagt gagagtgaaa gtgcatcaca agggaggaaa caggaggaaa agcgtcaaag 1440

cctattccac tggagtgcgt gctgaaaaac tttaaaaaaa gttttaatgg tgactatggg 1500

gttaagctaa cttcacagaa actgagaact tttttgagat aaaatagcca tcttttaatg 1560

tagggtggcc agccaagggg acaatagaca gggagataat tggccgagtg tttcgggtgg 1620

tcaccaggct tggagaacag cccgggcacc tggatcagtt tccgtatatt gactcctggc 1680

taagtataat tcagaccctc cctaagtggc tgcaggccta ctttgagatc tactgtaaga 1740

ctctaacggc caagacaaaa ccaggaacaa tagaaagaaa ctgcaaggca tcagaaaaag 1800

aaaagtcaca ggaaaagcag taaaaacctg tcctacaggc cccgcctgaa gagttagaaa 1860

ttccacccca ctatgcacca atttatccac ctctggcaaa gcttagacag aaggctgccc 1920

cggctgcctc cggagactca gactcagaag gaagcacccc tcaggcaaca ccacgcagag 1980

aggagccaga gcccttgact gaaaagccaa gggaggaact ccagggtgat gaggtcggcc 2040

gccttaggtc ggtccgtgcc caagcaatgc agatgccact ctgagaaaca tggggacaaa 2100

tttatttgaa tgcacagaat gaagtccaag ggggagaaca gctcttcttt tatcagccct 2160

tctctactac tgatctctta aattggagac aacatactcc ctcctataga gagaagcctc 2220

aggctcttat agatctaatg cagtccattt tcctaactca caatcctacc tgggttgatt 2280

gtaaacattt ttttctgtca ttatttaata tggaagagca ccgtagagtt atacaagctg 2340

ctctccagtg gctggagaaa aatgcatctt caagcacagg agatatcagg cagtatacac 2400

aacaagcact cctgatagag gctgacccag gctgggaccc taaccaggct caagggctac 2460

aagtttgcag cagtattgag aggcactcct aaatggaata aacgctggag agaaaaaggc 2520

caccaatatc ggaaaggtct cagaggttcg ccagaagcca gataaaagtc ccggtgaatt 2580

ttatgagagg ctgtgcgagg cttaccagct ttacatgcca cttgacccag aggctgcggg 2640

taatcagtgt atggttaatg tggcatttgt aagccaggtg caagaagaca tcggaagtta 2700

gaagggtttg aaggtgtgaa tattacccag cttatccagg tggctactaa ggtgtttgta 2760

aatcagaagg aggaggccaa gagaaaagct agatgcagag ctaaggaaaa ggcagacttg 2820

ctggcggtgg ccttagttgg aagagaaact ggttttgtga gaggatgtgg tcgtggttgc 2880

ggtcatgata gaggacaaac taggtaaaac caggaagcta agccaggaca agagggccaa 2940

cttaggctta agggagatca atgtgtgaga tgcaagcaga tgggacacta gaagaatgaa 3000

tgccaaattt tccggtgccc ttgttaggaa gagatttcct ccagaaattg caagcacaaa 3060

tctcctttat accagaaggg cacatgactc taaatctagg tcaaagaaaa gccatgataa 3120

agacccttac tgtcccaaca acagaggaat ggtaataatt tggg 3164

<210> SEQ ID NO: 29

<211> LENGTH: 1001

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (501)..(501)

<223> OTHER INFORMATION: s = c or g

<400> SEQENCE: 29

gaaccggagg ctaccggtgc atgctagtgt ttgtctgcac tttctcaggg tgggttgagg 60

catttcccac caggacaaag aaagctcggg aagtaaccag aatcttacta aaggacatta 120

ttcctagatt tcgactgcct ctaactttag gatcagacaa tggcccagca tttgtggcag 180

aaatagtaca acagctaaca cagaggttaa aaatcaaatg aaaactgcat acagcttatc 240

acccatagag ttctggaaag ttgaaagaat aaaccggaca ctcaaacagc cgttaaaaaa 300

gttttgccat gaaactcatc taagatggga tcaggtgctg cccatggtcc ttctctgagt 360

caggtgcacc cctactaaat taactgggta ttcaccctat aagatagtgt ttggccgaca 420

ccctgatcat aactcagata aacggggatt taaaaaattg gggaattaac cttaagaagg 480

caaatgcaag ccttaggtga sgtctcgcag gaaatgcaag gatgggtaag agaaagaata 540

cctgttagcc tcacagatgc agtacaaccc ttctaacctg gagactctgt ctgggtcaaa 600

caatggaacc caaccacttt agggccttta tgggatagtc cccatattgt gatcttgtct 660

actcccactg ctgttaaagt tgcaggtatc ataccttggg ttcatcatag ccggctgaaa 720

ccagaagcag ccaccaccca ggaccagtgg acaagtcaac aaaacccaga ccactcaaca 780

tggctgatcc tgtggtgaaa ccaagccact gctgacaagg acaactgccc tgcttcaacc 840

acaccagagg ctggttggtc cacgcacggc tgaagcttga ggaaacatcg agccctgttc 900

tagtcacaca aatggaagct gactagtcta tgcatggctg aagcctgagg aagtcaatga 960

tacataagta aatgtagact aaatttacaa acatagttat a 1001

<210> SEQ ID NO: 30

<211> LENGTH: 701

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (201)..(201)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 30

acctttgcaa aatcatgcaa tgttgcagtc agctcgtcag ttggataaat taatctgagt 60

gacctaggaa ttatctgctt cttaaggata catagatttc cctgagaaat catctgggtg 120

cttttggaat ttgggggcag aaaatacagg atagtattat ctgacaattt tctaattctt 180

ctatggtaat tagtgtgttt ygattttttt tttatctcat ctagattcag ttgctacaaa 240

gtatattttc tttagaagac tatccttttt attcatgcct ttaaatttat tggtacagag 300

ttgtgcaagt tattccttta tgatttattt aattctcctt tttctgtgac ttccctttta 360

taattttctg ttttgagtaa tgattttccc cttgttttct tagtaaattg gctggatatt 420

tattttcaaa tttcttttca aggaactaaa ttttgtagtt ttgtattcta ctttaaaaaa 480

agtcatgtct catttttatc tcctttacct ttaaaaattc cttccttttg tttttgtttt 540

atttaatttg ttggattttt caaaaaacaa aaactcctga gtcagatatt tgttctgttt 600

gttttattct ttattttata ccaatacaaa tttttacact aggaatttct ctgaaatgta 660

taagctccct cattggctct aaaatgtgat gttttctttt t 701

<210> SEQ ID NO: 31

<211> LENGTH: 501

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (251)..(251)

<223> OTHER INFORMATION: m = a or c

<400> SEQENCE: 31

ctctcttttt gctttgattt ctgggaggtg gattagcatt tactattaga ttcactattt 60

aatttactct ttaagaacaa agataaagtg tagccagaca actgcttagg agtgtatcag 120

tccaacaaga tgtacattga gctctaaaca aaatttaaaa atcttcatga gccttagaat 180

aagaaaaata ccttttacat tttaaaacag tgacttaaat tttttttttt ttttactgta 240

gcatatgagc mgccaccata actaacttat tttgtatttc tagcttcacc taaagctatt 300

tctggatgtg gctgctagtt tgtcaaagtt aaataaagcg tgacgcatat tgttcaaagg 360

caagcggaag atctaacgtt tctttttgaa atataggaaa ctggagatat caggcaacag 420

tggaaaagca tgcactttgg agaaaggtga aacctgaatt caattctctc aaaatgtact 480

tcgagcttca tccatttgca t 501

<210> SEQ ID NO: 32

<211> LENGTH: 1486

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (731)..(731)

<223> OTHER INFORMATION: s = c or g

<400> SEQENCE: 32

tgtttctttc tctataatac ataaaataaa ttatattaat attctaggtt atatataata 60

acacatataa ataaatataa aattatatta tatatagaaa tatatttttt atttttataa 120

gtacgtattt atttgtaaac tgtaaaacca taataaagga gtaaaactga catgaatata 180

agtgaaatgg agggggttgt gtagacaata tgtttagctg acaaatattt attgagcact 240

tgtcctatgc caggcactgt ctgaagttct gggaatacgc agggattaga caagttcttg 300

ttctcataga gctgatatcc tagtgtccgt ggcagggagg cagataataa actgacacat 360

cactattttg tcaggtggtg ctaagtgcca tggagacaca gtaggtgcag ggagggagaa 420

taatgggaag ataccattgc aggtaggggg tgaggaatag ccttgctgga cagggacata 480

tgaacaaagg tctgagttgg gtgaggcagg atgccacaca gacattggag gaggaaaatc 540

tgagcagggg gcacagcaaa gccccaaggc tgaggccaga tgaaggagca ggaggcaatg 600

tggctggaga ggagggagca aggggcagag tgttggtggt gaggtcaggg gcccagcagc 660

ctgatccagg ggacttgaac aggatggaag gactttgggt gcgttctgaa gaaggggaag 720

ccactggaag scattaagta gaaaaaattg gaagtgagag taattatatg tgaaagttgt 780

tagagtcaca atggagtgac gatgaggcag gacaggtagt caaggaagta agtgcagtta 840

acacaatgag ccccagtatt cgcattgtaa tccagctcat gcaagcacag ctatctcctg 900

cagggaatat ttcccataga cagcatttgc actttgattt tacctcttct caaacggacc 960

ctgttctcat gataatagta aaaaacacac ccctaggtgg agatttaaga tgctgatgaa 1020

ttatgagatg tatgaacaag catgtacagc tactgcacat gtgcacccag aggaccaccg 1080

aggacatgct tactagcaac accttttctc accctcttat gaataatcat gtaagagtcc 1140

cataaaagga tttctccagc aataatcagt gctgtccatt cagtggctca tgcctgtaac 1200

ccagcacttt gggaggccga ggtgggtgga tcacctgagg tcaggagttt gagaccagcc 1260

tggtcaacat ggtgaaacct cgtttctatt aaaaatacaa aaaaagtagc caggtgtaat 1320

ggcacatgcc tgtaatccca gctacttggg aggctgaagc aggagaactg attgaacctg 1380

ggaggtggag gttgcagtga gtcatgactg tgccactgca ctccagccaa cagagtaaga 1440

ctctgttccc cctcggcccc ctgcaaaaaa aaataataac aatgat 1486

<210> SEQ ID NO: 33

<211> LENGTH: 4000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (2000)..(2000)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 33

tttgttatgg acttatagca attatttata caaaacataa gaattgttct gaaaaaatta 60

aaaaatatat acctgcatgg ctcataactg gaaatattat accaggaggc tttgtcactt 120

ggtatcttta tccttttact tattattttc ttttaattct acaggaagca gtaaattctt 180

tatggttgga gtggatgaag aggtgccatg taatagctca gaaggcaaag tcccttgttt 240

taccagctgt ttaggcatcc atgtactcat ccttgatttg aagggtttga gttaattcta 300

tccttccaaa tcagccctta caatctcacg tgcccacctc ttctgcaaca gtctctgggc 360

ctagagggag gacgcttgca atacaggatt ttttgcatgt tcccagtggc tccaccccat 420

tctcccagtg cacatgcagg cccttagtct gaacccacgc tacattgatt tatttccctt 480

actgagcatg tgttaaggga tggaattttt caccatgggc atgtttaggc aagccccctg 540

tacacaatgt cctggatggc atttggctgt cttctgcctc tatcattccc ccatctaaaa 600

gagtacatct aactgccatt agaataagga taagaagaaa gacaaagacc catcttaact 660

gctttctgct gacagagggc actgttttgg aaagacagca gttgggtctc cctcagaggc 720

ctatctaagg gtatctggta aaagggacca tcattcgagg ctctggttgc ataactgttt 780

ggagtttgag ggcctgaagg cgagaagaga caaaccaggt tattagaaga catgtaccaa 840

aatgaaatgg gggaagggta aggacagttc aaaaatcctg aggctgctga catgcccaga 900

taactggtag ctgtagttgt gcctgctaag atttgggtgc atgggacttg gctttggtta 960

gctcccgtag tttattttcc caaaaaagaa acctctgggt tatgggcacc ctatttactc 1020

ccattatctg gcaggatttg taggataatt gttcagaact agaatactgt tccagatttt 1080

tacattaccc atgccttttg tttcttctga gctgcagcca gagatcactg gttagttcac 1140

aggaataagc agggttaatt taaaatgtag gcaaaaaact taaaaacaac taatgagtct 1200

agaatttaat gacaaatgta tgataagttt tgaaacataa tttctttctc cccagtcctc 1260

atttttgtta aaaacaaatc ataataggag tgagttgttt gtaaaataaa ctttagtctt 1320

acacttggtc tgcttatttg cacaaagtac aacaagaata attattttta cataggcttt 1380

ttaaattggc tttgatggaa ctctgttcca caaggaattt cagataggac ttcataaaaa 1440

tgagcccagc catgggtttg taccctctaa tacctatgag ttgggtgaat tgctctcttc 1500

ttgaggtccc aagaatatgc ggttcctggc cctgttagaa agtgacattc tttactcact 1560

acaggttagg gaacctgtat ggggactgtg tagacaaagt atgaggctgg tttacccaag 1620

gggcttttat tggctctgca agttgagctt gattccttaa agggaaacat acccttccag 1680

tcaaagttac agttactggt tggtaaagtt aaagttacag ctactggttg ctaaagcaac 1740

cagtttctcc aattgcatcc tgttgcaaaa gaaagtggat tcttactgca ctgatgcaaa 1800

taaccgtatt gccctaagtt aagaatactc acagatagtt tccaaattct agaggaagca 1860

ggcagagaga aaaaaaagtg ctaaattttg ttcataggag tctgcattac tcaattatta 1920

aagattgtgt atagctcaaa aaaaaagatc agcactgttt taagctaaag tttaaaaaag 1980

attacttcaa ttttctattr gttcagtctg ttcagttaac tcttgttctg cttgatattt 2040

gtgaacattt cagctcttca tgagtcctgt acgtttttcc attattccaa tgtcacaatc 2100

tccaaagtta tcagaaacct gcatttgaga gcacctgtta cgtttctata gctgattata 2160

aatcctattt gaagaagatc aaaacaaaac aatggtctgt gaatagcaaa atgtccatgg 2220

tagttacagt caaaaacaca attgacaaag aaattttgtt atctctgtgg cttataatca 2280

cctaacataa cacctttaat tgtgagtgat agcatatact tagatattag aattttagaa 2340

atcccataca gttttggagc atatattatt attcactaaa atataaccca aagaagatta 2400

aatatcattt tggcaatccc atgtacataa atttgtcagg taatcctatt tacctctctt 2460

ctggatgctc cagggatgct aggggtcagg aaagacaacc ttgaagctga catttgattt 2520

tgggaagccc attaaatatg ttagaggttt aaaacaatgt tatgaagtag aattccagat 2580

taccataaat tacttatttt gccaaaatga tgactcaaaa attttaaaac aagccaaaaa 2640

cttttactca tttagaggga agacttagat ttccaaagaa tttgtctcct gtcttcactt 2700

tcatttcctt ggcagtctat ctggaagaca aactgaaata tttaattatc ctttactatt 2760

acatgaaaat cttatacaag ggagagaaag ccaaatttta ccctcacatt agtttactat 2820

taatgtcaac cccaattttt taatgaaacc ttatagacaa ttctatccaa tcttaaccag 2880

tttgatcatg aggtaagatt cctgtaagcc ttttataacc ttttacaaat tactaattta 2940

ctaatctgct aaagagcaga ttagggcttt aagaaaacct tgttgtgctt tcatttcaat 3000

gctcagtttg tagaaaaacc atataataga gttttggatt taatcaatgt tcacacacag 3060

aatttctttt gcaagattaa tttttagaaa cctcccacaa cttgtttaaa cctttagttt 3120

atcttatcta atttataata gtcctttaac cttaggcaaa aacttacatt tccatgcatt 3180

cttataatct ttgactaata acacatttta ctgttcttac ataccttgca tgtaaatcta 3240

ttttcagtgg tctcaattac atgttataat ggtacctctt agcacttttt aattttagtt 3300

taaaacctgg taagtcgttt taattacgca ctaggtgctg ataaagtttg attccttcca 3360

gcataattaa gggtgtggtt aattccatat gtccctgtgc cttaccaagt tgtaaagcag 3420

gcagattgaa cagttttcaa aggcaaaaga agccgtttac aaccttaaaa catttagcca 3480

cctagtgcct gacttgcata atttagacca gctatttaca ttttaagaac atttgcattt 3540

tatcaattat ctttaagact acttttattt ctcagagatt aaagtcacaa gaactaaaag 3600

gcattatagc ttttatcttt cctccaaaaa tatttgatct tagtgctgat ttttctttaa 3660

gccaattaat tagagctctt ttttataact acacagatgg agaagaagat tgagtgttat 3720

aagatttttc atttgcccat ctcctaattg gattcttggt ctctgggtgg gaccctttaa 3780

gagcagggct aagaaagcat gcagtttatt ttcttttttt ctttttcttt tctttttttt 3840

tgagaaagag tttcactctt gttgcccagg ctggagtgca atggtgcgat ctcagctcac 3900

tgcaacctct gcctcccagg ttcaagcgat tctcttacct cagcctccca agtggctgca 3960

tgcagtttct agggcctaat aaacaggcat agctggaaaa 4000

<210> SEQ ID NO: 34

<211> LENGTH: 4000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (2000)..(2000)

<223> OTHER INFORMATION: w = a or t

<400> SEQENCE: 34

cagctactgg ttgctaaagc aaccagtttc tccaattgca tcctgttgca aaagaaagtg 60

gattcttact gcactgatgc aaataaccgt attgccctaa gttaagaata ctcacagata 120

gtttccaaat tctagaggaa gcaggcagag agaaaaaaaa gtgctaaatt ttgttcatag 180

gagtctgcat tactcaatta ttaaagattg tgtatagctc aaaaaaaaag atcagcactg 240

ttttaagcta aagtttaaaa aagattactt caattttcta ttagttcagt ctgttcagtt 300

aactcttgtt ctgcttgata tttgtgaaca tttcagctct tcatgagtcc tgtacgtttt 360

tccattattc caatgtcaca atctccaaag ttatcagaaa cctgcatttg agagcacctg 420

ttacgtttct atagctgatt ataaatccta tttgaagaag atcaaaacaa aacaatggtc 480

tgtgaatagc aaaatgtcca tggtagttac agtcaaaaac acaattgaca aagaaatttt 540

gttatctctg tggcttataa tcacctaaca taacaccttt aattgtgagt gatagcatat 600

acttagatat tagaatttta gaaatcccat acagttttgg agcatatatt attattcact 660

aaaatataac ccaaagaaga ttaaatatca ttttggcaat cccatgtaca taaatttgtc 720

aggtaatcct atttacctct cttctggatg ctccagggat gctaggggtc aggaaagaca 780

accttgaagc tgacatttga ttttgggaag cccattaaat atgttagagg tttaaaacaa 840

tgttatgaag tagaattcca gattaccata aattacttat tttgccaaaa tgatgactca 900

aaaattttaa aacaagccaa aaacttttac tcatttagag ggaagactta gatttccaaa 960

gaatttgtct cctgtcttca ctttcatttc cttggcagtc tatctggaag acaaactgaa 1020

atatttaatt atcctttact attacatgaa aatcttatac aagggagaga aagccaaatt 1080

ttaccctcac attagtttac tattaatgtc aaccccaatt ttttaatgaa accttataga 1140

caattctatc caatcttaac cagtttgatc atgaggtaag attcctgtaa gccttttata 1200

accttttaca aattactaat ttactaatct gctaaagagc agattagggc tttaagaaaa 1260

ccttgttgtg ctttcatttc aatgctcagt ttgtagaaaa accatataat agagttttgg 1320

atttaatcaa tgttcacaca cagaatttct tttgcaagat taatttttag aaacctccca 1380

caacttgttt aaacctttag tttatcttat ctaatttata atagtccttt aaccttaggc 1440

aaaaacttac atttccatgc attcttataa tctttgacta ataacacatt ttactgttct 1500

tacatacctt gcatgtaaat ctattttcag tggtctcaat tacatgttat aatggtacct 1560

cttagcactt tttaatttta gtttaaaacc tggtaagtcg ttttaattac gcactaggtg 1620

ctgataaagt ttgattcctt ccagcataat taagggtgtg gttaattcca tatgtccctg 1680

tgccttacca agttgtaaag caggcagatt gaacagtttt caaaggcaaa agaagccgtt 1740

tacaacctta aaacatttag ccacctagtg cctgacttgc ataatttaga ccagctattt 1800

acattttaag aacatttgca ttttatcaat tatctttaag actactttta tttctcagag 1860

attaaagtca caagaactaa aaggcattat agcttttatc tttcctccaa aaatatttga 1920

tcttagtgct gatttttctt taagccaatt aattagagct cttttttata actacacaga 1980

tggagaagaa gattgagtgw tataagattt ttcatttgcc catctcctaa ttggattctt 2040

ggtctctggg tgggaccctt taagagcagg gctaagaaag catgcagttt attttctttt 2100

tttctttttc ttttcttttt ttttgagaaa gagtttcact cttgttgccc aggctggagt 2160

gcaatggtgc gatctcagct cactgcaacc tctgcctccc aggttcaagc gattctctta 2220

cctcagcctc ccaagtggct gcatgcagtt tctagggcct aataaacagg catagctgga 2280

aaacaaaaac ggattttgag agcgatctat ttgcctctaa ttcctggggt tccatgagga 2340

aaacagaggt ttctcccaaa atggaatcca tggtgccttt tctgttttta ccaagcagcc 2400

ctatgccatc agaaattatc ttagggcctc tcatgtgcgc attaacactg gcaagacaag 2460

gtggagaaaa gtaattcagt caactgagaa aaaaatcttt ttccagcaaa acaagatcca 2520

agaagagaaa aacataaagg cctttcaaat atacgtatag cttggatatc cacttttaat 2580

taagctgagc tctctttaag aaagtccttt taaatcccac attacctgac ttcagccatg 2640

ccaagcagcc aatatttctg gctttggaag tttatcaaaa gaacctcaag gttcaaccaa 2700

caagcctcaa ttaagacacg cgaagcacac cagattggct acaccttaag accagcctca 2760

taaaaccttt ttcactaatg gaaactttac agggaatatc aacagtgatc cttatcattc 2820

ttttcaccag tttacacagg gagagagagg ccaaaagtct gactggttaa aaaactttta 2880

tccttttgct ggcatgtcat gcttctgggt tcccttcccc tgagctcaat tctaagccaa 2940

ccagtttaag gtttgggaaa ttaacttttc tcagtttgga ggatgcatcc tatgggaatg 3000

tcctttagta cagggacaca gtcacccatc tgtgaagaga ggacaaagga ggaaaaagta 3060

aaaaaagatt tttttcaaag gctccccagg ggttcaggat gcatttgaaa gggggacaga 3120

ttgaagatga atggctactc atctagaaag aggggagcca gacatccctg gttcctttct 3180

ctttctagga aatagccagg gtatgtgagg gaaagaagga acaagcatcc attttccttc 3240

ttccgtcctt atgtccccaa gtcctgacaa cctcgacagg gtgccaccca tgggtgccaa 3300

tacggttctc acccatggta acaggggacc tagtggatgg gattatccac tgttacccac 3360

aaactgtctt tccccctgct ctcaatagcc ttcaagtgcc ctagacctca tttaggccat 3420

tgatactagt atgaccttta tccatgaaac aagaggcttg gcttaattgt caggaattag 3480

tcatgctcac ctatactgtg ctttttaatt tttgttgttg tctgcctctg gatccctccg 3540

atgcagttat ctttcctagg gcttctacat gaagcttgga attgagtttg ggacaaaaga 3600

actgcctcag taggtgggtg catggactca tcaatcccca ggtgtccctc accagtctgg 3660

ctgctgccgc cttatcataa gctgaaggct aaggtgcaac tgtgaaatta ggtccttctc 3720

aaacaaggga gggaaaatgg tgtcctgtga attagggtcc tggtctaata agatgccttc 3780

caaaaggaag aaaacttctg gcacagagaa gacccctcta cccgcagggc tgtgttatta 3840

ggttggtgcg aaagcaattg tggtgcccat cattctaagt aatgacaaaa accacaacta 3900

ctttcacacc agcctactaa ctcatgactt ggtggacaaa agaaaataac aacaacaaca 3960

acagcttaaa tgcagggctg tgtttactgc tgacaaggtg 4000

<210> SEQ ID NO: 35

<211> LENGTH: 1191

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (819)..(819)

<223> OTHER INFORMATION: r = a or g

<400> SEQENCE: 35

tgctagattt tgcaattgat tgcaaaatca gttttgcaat cagttgcaag tttcttgacc 60

cattcactgg attgtgattg tgttacaaga ccaagtcaag attatttgac ctcatagcac 120

tttactcttt aacagctctc tccttgaaat attaccttcc cgcactattc atgaacatat 180

cagcccacag atttcctcct acctctttgg ctattccttc tcagtctcct tttaagattt 240

ttcttactca ggcatctttg ggtgaaagtc cctcaatatc tggtcttact caaaactgcc 300

tctcactcac tactctctcc ctaggcaatc ctatcaatgt ccactgtact gtatgcatga 360

aatgactcac aaatttttgt ctctaataaa gactttactt tgagtcttgg atctgaagag 420

atatgtcccc tggatctctt aaaagcatat taagcttaac atattcaaaa ccaaactcat 480

aatctctatt accttgcatc ccaccaaact ggtctttttc atcaaacccc atcaaaaaga 540

tctcagcaat tcatctaatt atgcatgcaa gaaacttaga ggtcatcttt gacatgtcct 600

cttcaccatt atatccgatc tatcacctgg tcctgccaat gttgcttact aaatgtccct 660

ccaggaataa attttctcta gtccttttca taagccaaat tcggtctcct gtagactatt 720

attagtaacc tgctacttca cttatctgca tccaacctgt tccccaaaat atagtcaaaa 780

tgatcttttc tatacacaag tctgatcata tggctcctra ataaaattat gtttttctgg 840

aggaagtcac aactccttaa aaaattcttg tacctgccta cctttccagt cccatctcat 900

tatggactcc ttcctgcatg ctcttcttca atatattggt tatctttcag tcccttgagt 960

ttgctatgcc agagggcctt tgcaaatgct ggtcccttgc ttgaaatgct ctattctttg 1020

cctcaagtga tcctcctacc tcggcctccc aaagtgctgg gattacaggc atggagccaa 1080

cacacctggc cttcacatct atttttaatc caagtaattc tagggtcaaa taatactgaa 1140

atctcgctaa gtatcaaacg ctgcttttaa ctgaagaaag tttactttgt t 1191

<210> SEQ ID NO: 36

<211> LENGTH: 844

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (501)..(501)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 36

atttcctcaa cagaaaattc ctgtaatcag tattttcatg aacttaaccc tcgtgtttgg 60

ggaaggacta ggcactatga caaattctgc tgtctaaaaa tactttttta ggggctgggc 120

atggtggctc acacccataa tcccagcact ttgggaggcc aaagggggca gatcacctga 180

ggtcaggagt ttgaaaccag cctggccaat atgatgaaac cccgtctcta ctaaaaatac 240

aaaaattagc caagggtggt ggcacacact tgtaatccta gctactcggg aggcagaggc 300

cggagaatcg cttgaacccg ggatgcagag gttgcagtga gccaagatcg tgccactgca 360

ctccagcctg ggtgacaaag cgagaccctg tcacacacaa acacacacac acacacacac 420

acacaaggtg acaaattgat ggagtggagg ctctgcagtc agatatagca aatttgaacc 480

ctgacttgga taatacagat ygcgagattg gagcaatgac taaagcctct acatcttgat 540

gttctggact agaaaattag gataataaaa gctatctcct agagttgttc tgacaattag 600

accaaaagag ataatgatgt agagacctca gcaaagcaca aggcctagtc actagccgtg 660

ctccgggagg gctgtccaaa agcaggaaga acaagggcaa agaaactcca tggaactcac 720

tttcccacca gggagtgaac cgcggcgtca tgctccattc tgagtagctc ccagccgagg 780

ccgccctcac cctcccgtaa taaggttcct gtatgtctga ggtttcactg gtaaggtcac 840

aaga 844

<210> SEQ ID NO: 37

<211> LENGTH: 801

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (401)..(401)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 37

aaggtttccc aaaatattta ttgaaagact tgaaatctag ctttctagac acataataag 60

gaagatagac ggtatctata ctcggtaatc tacatggtga cagcagtttc attccatcac 120

aattaaagca gaaccacaac atatattgag tataatttga tgttttaaaa ttattattta 180

tttataataa gtcttgaact tagctgtaat gacagacttc tcttttaaaa taatatctca 240

ttgtttatcc tattctaaac gcaagggata taacagtatt atagcccatg aactggatac 300

accaaagtga aagttttcaa aattataaat ttgtcttgtg ctgttgaaaa tcccttagag 360

acaggaatgg attcaggtat tctggggtct gaaatttata yaatcttggt ccatttaatg 420

tttctataac agaacacctg aggctaggta attgataagg aaaagaggtg tacttagcca 480

atgttctgca gcctgggaag ttacaagaaa tgtgctgcca gcatccactt ggcttctggt 540

gagagctttt catgctgcat gagaacatgc tagagaaggt caatggggaa aacagatcgt 600

gtgaagaggc caaactcaag gggcatcctg gctttacaac aaccactctc atagaaacat 660

ttccatgaca aattcagtct tgcaagagtg agaactcact caactgcagc aataatggta 720

ccaagccatt catgagtgct ccatccccat gacccaaaca cctcctacga ggccctactt 780

ccaacaccac cacactaagg a 801

<210> SEQ ID NO: 38

<211> LENGTH: 801

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (401)..(401)

<223> OTHER INFORMATION: y = c or t

<400> SEQENCE: 38

atattaagct tttcttttct gtttgttttt gttttgttta gtttttaatc ctgtcttaga 60

agaacttatc tttattctca aaattaaatg taattttttt agtgacaaag aagaaaggaa 120

acctcattac tcaatccttc tggccaagag tgtcttgctt gtggcgcctt cctcatctct 180

atataggagg atcccatgaa tgatggttta ttgggaactg ctggggtcga ccccatacag 240

agaactcagc ttgaagctgg aagcacacag tgggtagcag gagaaggacc ggtgttggta 300

ggtgcctaca gagactatag agctagacaa agccctccaa actggcccct cctgctcact 360

gcctctcctg agtagaaatc tggtgaccta aggctcagtg yggtcaacag aaagctgcct 420

tcttcacttg aggctaagtc ttcatatatg tttaaggttg tctttctagt gaggagatac 480

atatcagaga acatttgtac aattccccat gaaaattgct ccaaagttga taacaatata 540

gtcggtgctt ctagttatat gcaagtactc agtgataaat ggattaaaaa atattcagaa 600

atgtattggg gggtggagga gaataagagg cagagcaaga gctagagaat tggtttcctt 660

gcttccctgt atgctcagaa aacattgatt tgagcataga cgcagagact gaaaaaaaaa 720

tttactttga tctctgtttt tgaattctta ttatttatat tttgcttact accttttttg 780

ccttttgtcc ttttgtggag a 801

<210> SEQ ID NO: 39

<211> LENGTH: 701

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: allele

<222> LOCATION: (501)..(501)

<223> OTHER INFORMATION: s = c or g

<400> SEQENCE: 39

atttgagggc aagcaagggg tctgtgtgct ggagaagagt gaggaaggtg agaattaggg 60

agtgaggcct gggagattat gaggaaagga aacagatcat acagcgcctt ggaggccatt 120

ataaagactt tggtttttac ccttatgaga tgggaagcta ttggcggttt tagagcagga 180

aagtgacatg atctgattta tgttccaagg ctcatgctgg ccaccttgtt aagacaaaac 240

tggagggagg caagcagagc ggggacacca atgaggtaac catagtgacc atccagagga 300

gaaatgatgg tggcctggaa taggtagttc tgagaagtgt tgtattttgg aggtagatca 360

atagaattta ttggtgcatt gaatatatat gatgtgaaag aaagcgggga gacaaagata 420

acctcaacgc ttttggcctg agcagctgta agactgggat tgcatttgat cacagggcaa 480

gctcagtcgg gctcaaaact stttgctcct tcctggctgg aacttcgtgt gggcctaaga 540

tgtttaactg gaatttcatc tggcagactt aaacattgtg ttcttctttt aaaagctcaa 600

ataacaaata ttccaaaatg taaagcaaaa aaaggattta ttgaaatcat gtgacaatat 660

atccctaaca ccatgaagaa gatgacaatt atgatttcca t 701

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Citation

Patents Cited in This Cited by
Title Current Assignee Application Date Publication Date
Fibrosis susceptibility gene and uses thereof UNIVERSITE D'AIX-MARSEILLE,INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE) 18 February 2010 29 March 2016
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Fibrosis susceptibility gene and uses thereof UNIVERSITE D'AIX-MARSEILLE,INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE) 18 February 2010 31 May 2012
Methods and compositions for diagnosing and treating neuropsychiatric disorders such as schizophrenia MILLENNIUM PHARMACEUTICALS, INC. 19 April 2002 15 May 2003
Anti-il-22ra antibodies and binding partners and methods of using in inflammation ZYMOGENETICS, INC.,XU, WENFENG,KINDSVOGEL, WAYNE,CHANDRASEKHER, YASMIN, A.,DILLON, STACEY, R. 24 March 2004 07 October 2004
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US10150989 Fibrosis susceptibility IL22RA2 gene 1 US10150989 Fibrosis susceptibility IL22RA2 gene 2 US10150989 Fibrosis susceptibility IL22RA2 gene 3