Genetic polymorphisms associated with liver fibrosis methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with liver fibrosis and related pathologies. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

1 . A method for identifying an individual who has an altered risk for developing liver fibrosis, comprising detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-261 and 523-34256 in said individual's nucleic acids, wherein the presence of the SNP is correlated with an altered risk for liver fibrosis in said individual. 
     
     
         2 . The method of  claim 1  in which the altered risk is an increased risk. 
     
     
         3 . The method of  claim 1  in which the altered risk is a decreased risk. 
     
     
         4 . The method of  claim 1 , wherein the SNP is selected from the group consisting of the SNPs set forth in Tables 6 and 7. 
     
     
         5 . The method of  claim 1  in which detection is carried out by a process selected from the group consisting of: allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism. 
     
     
         6 . An isolated nucleic acid molecule comprising at least 8 contiguous nucleotides wherein one of the nucleotides is a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences in SEQ ID NOS: 1-261 and 523-34256, or a complement thereof. 
     
     
         7 . The isolated nucleic acid molecule of  claim 6 , wherein the SNP is selected from the group consisting of the SNPs set forth in Tables 3 and 4. 
     
     
         8 . An isolated nucleic acid molecule that encodes any one of the amino acid sequences in SEQ ID NOS:262-522. 
     
     
         9 . An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:262-522. 
     
     
         10 . An antibody that specifically binds to a polypeptide of  claim 9 , or an antigen-binding fragment thereof. 
     
     
         11 . An amplified polynucleotide containing a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences of SEQ ID NOS: 1-261 and 523-34256, or a complement thereof, wherein the amplified polynucleotide is between about 16 and about 1,000 nucleotides in length. 
     
     
         12 . An isolated polynucleotide which specifically hybridizes to a nucleic acid molecule containing a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences in SEQ ID NOS: 1-261 and 523-34256. 
     
     
         13 . The polynucleotide of  claim 12 , which is an allele-specific probe. 
     
     
         14 . The polynucleotide of  claim 12 , which is an allele-specific primer. 
     
     
         15 . The polynucleotide of  claim 12 , wherein the polynucleotide comprises a nucleotide sequence selected from the group consisting of the primer sequences set forth in Table 5 (SEQ ID NOS:34257-34458). 
     
     
         16 . A kit for detecting a single nucleotide polymorphism (SNP) in a nucleic acid, comprising the polynucleotide of  claim 12 , a buffer, and an enzyme. 
     
     
         17 . A method for identifying an agent useful in therapeutically or prophylactically treating liver fibrosis, comprising contacting the polypeptide of  claim 9  with a candidate agent under conditions suitable to allow formation of a binding complex between the polypeptide and the candidate agent, and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent. 
     
     
         18 . A method for identifying an individual who has a risk for progressing rapidly from minimal fibrosis to bridging fibrosis/cirrhosis, comprising detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-261 and 523-34256 in said individual's nucleic acids, wherein the presence of the SNP is correlated with a risk for a rapid rate of progression to bridging fibrosis/cirrhosis in said individual.