During the current reporting period we have continued our collaborative genotyping studies as part of the North American Rheumatoid Arthritis Consortium, resulting in the publication of a manuscript in Nature Genetics in June 2010. To identify new genetic risk factors for rheumatoid arthritis, NARAC conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P less than 5 times 10 to the negative eighth power) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST (IL-6 signal transducer, or gp130, a receptor subunit for several cytokines, including IL-6 and IL-11), SPRED2 (regulates growth factor-induced activation of the MAP kinase cascade), RBPJ (recombination signal-binding protein for immunoglobulin kappa J region), CCR6 (a chemokine receptor), IRF5 (interferon regulatory factor 5, a transcription factor that can mediate viral induction of interferon), and PXK (a serine/threonine kinase). We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3 (a nuclear transcriptional activator preferentially expressed in lymphoid tissue). These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P less than 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.
