Genetic polymorphisms associated with rheumatoid arthritis, methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with rheumatoid arthritis. 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.

What is claimed is: 
     
         1 . A method of determining whether a human has an increased risk for developing rheumatoid arthritis, comprising testing nucleic acid from said human for the presence or absence of a polymorphism in said human's nucleic acid, wherein said polymorphism is at position 101 of any of SEQ ID NOS:10,916-49,582 and 50,231, and correlating the presence or absence of said polymorphism with said human having an increased risk for developing rheumatoid arthritis. 
     
     
         2 . The method of  claim 1 , wherein said nucleic acid is a nucleic acid extract from a biological sample from said human. 
     
     
         3 . The method of  claim 2 , wherein said biological sample is blood, saliva, or buccal cells. 
     
     
         4 . The method of  claim 2 , further comprising preparing said nucleic acid extract from said biological sample prior to said testing step. 
     
     
         5 . The method of  claim 4 , further comprising obtaining said biological sample from said human prior to said preparing step. 
     
     
         6 . The method of  claim 1 , wherein said testing step comprises nucleic acid amplification. 
     
     
         7 . The method of  claim 6 , wherein said nucleic acid amplification is carried out by polymerase chain reaction. 
     
     
         8 . The method of  claim 1 , wherein said correlating step is performed by computer software. 
     
     
         9 . The method of  claim 1 , wherein said testing 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, single-stranded conformation polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE). 
     
     
         10 . A method of determining whether a human has an increased risk for developing rheumatoid arthritis, comprising testing nucleic acid from said human for the presence or absence of an LD polymorphism in said human's nucleic acid, wherein said LD polymorphism is in linkage disequilibrium with a polymorphism at position 101 of any of SEQ ID NOS:10,916-49,582 and 50,231, and correlating the presence or absence of said LD polymorphism with said human having an increased risk for developing rheumatoid arthritis. 
     
     
         11 . An isolated polynucleotide which specifically hybridizes to a segment of a nucleic acid molecule, wherein said segment includes a polymorphism at position 101 of any of SEQ ID NOS:10,916-49,582 and 50,231. 
     
     
         12 . A kit for detecting a polymorphism in a nucleic acid, comprising the polynucleotide of  claim 11 , a buffer, and an enzyme. 
     
     
         13 . An isolated polypeptide encoded by the polynucleotide of  claim 11 , wherein the polypeptide comprises an amino acid sequence selected from the group of SEQ ID NOS:670-1338. 
     
     
         14 . An antibody that selectively binds to the polypeptide of  claim 13 . 
     
     
         15 . A method for identifying an agent useful in therapeutically or prophylactically treating rheumatoid arthritis, comprising contacting the polypeptide of  claim 13  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. 
     
     
         16 . The method of  claim 15 , further comprising determining whether said agent modulates the function or activity of said polypeptide. 
     
     
         17 . A pharmaceutical composition comprising an agent identified by the method of  claim 15  and a pharmaceutically acceptable carrier therefor. 
     
     
         18 . A method for treating rheumatoid arthritis, comprising administering to a human in need of such treatment a pharmaceutically effective amount of an agent identified by the method of  claim 15 . 
     
     
         19 . The method of  claim 1 , further comprising administering a therapeutic agent to said human to mitigate said increased risk for developing rheumatoid arthritis. 
     
     
         20 . A method for conducting a clinical trial in which a therapeutic agent is evaluated in at least one human, the method comprising testing nucleic acid from said human for the presence or absence of a polymorphism in said human's nucleic acid, wherein said polymorphism is at position 101 of any of SEQ ID NOS:10,916-49,582 and 50,231, and determining whether to include or exclude said human in said clinical trial based on said genotype.