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

Abstract

The present invention provides compositions and methods based on genetic polymorphisms that are associated with autoimmune disease, particularly rheumatoid arthritis. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules 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 altered risk for rheumatoid arthritis, comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:526, 92-525, and 527-584 or its complement, wherein the polymorphism indicates an altered risk for rheumatoid arthritis. 
     
     
         2 . The method of  claim 1 , wherein the altered risk is an increased risk or a decreased risk. 
     
     
         3 . The method of  claim 1 , wherein said nucleic acid is a nucleic acid extract from a biological sample from said human. 
     
     
         4 . The method of  claim 3 , wherein said biological sample is blood, saliva, or buccal cells. 
     
     
         5 . The method of  claim 3 , further comprising preparing said nucleic acid extract from said biological sample prior to said testing step. 
     
     
         6 . The method of  claim 3 , further comprising obtaining said biological sample from said human prior to said preparing step. 
     
     
         7 . The method of  claim 1 , wherein said testing step comprises nucleic acid amplification. 
     
     
         8 . The method of  claim 7 , wherein said nucleic acid amplification is carried out by polymerase chain reaction. 
     
     
         9 . The method of  claim 1 , further comprising correlating the presence of the polymorphism with an altered risk for rheumatoid arthritis. 
     
     
         10 . The method of  claim 9 , wherein said correlating step is performed by computer software. 
     
     
         11 . The method of  claim 1 , wherein said testing is performed using sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, or denaturing gradient gel electrophoresis (DGGE). 
     
     
         12 . The method of any one of  claim 1 , wherein said testing is performed using an allele-specific method. 
     
     
         13 . The method of  claim 12 , wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification. 
     
     
         14 . The method of  claim 1  which is an automated method. 
     
     
         15 . A method of determining whether a human has an altered risk for rheumatoid arthritis, comprising testing nucleic acid from said human for the presence or absence of a first polymorphism which is in linkage disequilibrium with a second polymorphism, wherein the second polymorphism is a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:92-584 or its complement, and wherein the first polymorphism indicates an altered risk for rheumatoid arthritis. 
     
     
         16 . The method of  claim 15 , wherein the altered risk is an increased risk or a decreased risk. 
     
     
         17 . The method of  claim 15 , wherein the first polymorphism is selected from the group consisting of the polymorphisms in Table 4. 
     
     
         18 . The method of  claim 1 , wherein said polymorphism comprises at least one polymorphism selected from the group consisting of rs2239657, rs7021880, and rs7021049. 
     
     
         19 . The method of  claim 18 , wherein said polymorphism comprises a haplotype selected from the group consisting of rs2239657(G)-rs7021880(C)-rs7021049(G) and rs2239657(A)-rs7021880(G)-rs7021049(T). 
     
     
         20 . The method of  claim 19 , wherein the rs2239657(G)-rs7021880(C)-rs7021049(G) haplotype indicates an increased risk for rheumatoid arthritis and the rs2239657(A)-rs7021880(G)-rs7021049(T) haplotype indicates a decreased risk for rheumatoid arthritis. 
     
     
         21 . The method of  claim 18 , wherein said polymorphism comprises a diplotype selected from the group consisting of rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) and rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T). 
     
     
         22 . The method of  claim 21 , wherein the rs2239657(G)-rs7021880(C)-rs7021049(G)/rs2239657(G)-rs7021880(C)-rs7021049(G) diplotype indicates an increased risk for rheumatoid arthritis and the rs2239657(A)-rs7021880(G)-rs7021049(T)/rs2239657(A)-rs7021880(G)-rs7021049(T) diplotype indicates a decreased risk for rheumatoid arthritis. 
     
     
         23 . The method of  claim 18 , further comprising testing nucleic acid from said human for at least one other polymorphism selected from the group consisting of PTPN22 R620 W and HLA-DRB 1, wherein the PTPN22 R620 allele (CC genotype) and 0SE at HLA-DRB 1 indicate a decreased risk for rheumatoid arthritis, and the PTPN22 W620 allele (TT or TC genotype) and 2SE at HLA-DRB 1 indicate an increased risk for rheumatoid arthritis. 
     
     
         24 . A method of reducing the risk of rheumatoid arthritis in a human, comprising administering to said human an effective amount of a therapeutic agent, said human having been identified as having an increased risk for rheumatoid arthritis due to the presence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:92-584 or its complement. 
     
     
         25 . The method of  claim 24 , wherein said therapeutic agent comprises a TNF inhibitor. 
     
     
         26 . A method of reducing the risk of rheumatoid arthritis in a human, comprising:
 (a) identifying a human who has an increased risk for rheumatoid arthritis due to the presence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:92-584 or its complement; and   (b) administering to said human an effective amount of a therapeutic agent, thereby reducing the risk of rheumatoid arthritis in said human.   
     
     
         27 . The method of  claim 26 , wherein said therapeutic agent comprises a TNF inhibitor. 
     
     
         28 . The method of  claim 26 , wherein step (a) comprises testing nucleic acid from said human for the presence or absence of said polymorphism. 
     
     
         29 . The method of  claim 12  in which said testing is carried out by using an allele-specific primer selected from the group consisting of the allele-specific primers in Table 3. 
     
     
         30 . The method of  claim 1 , further comprising selecting said human for inclusion in a clinical trial of a therapeutic agent. 
     
     
         31 . The method of  claim 30 , wherein said therapeutic agent comprises a TNF inhibitor. 
     
     
         32 . A kit for carrying out the method of  claim 1 , wherein the kit comprises at least one polynucleotide detection reagent, and wherein the polynucleotide detection reagent selectively hybridizes to said nucleic acid in the presence of said polymorphism and does not hybridize to said nucleic acid in the absence of said polymorphism.