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Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably  HLA-DRB1  and  PTPN22 , these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR common  = 1.28, trend P comb  = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from  MEGF9  to  STOM  on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P comb <0.01) spanned a large 525 kb region from  FBXW2  to  GSN . However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of  PHF19  across  TRAF1  into the  TRAF1-C5  intergenic region, but excluding the  C5  coding region, as the most interesting (trend P comb : 1.45E-06 → 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors,  HLA-DRB1  and  PTPN22 , the variants reported here generate more than a 45-fold RA-risk differential.

A Large-Scale Rheumatoid Arthritis Genetic Study Identifies Association at Chromosome 9q33.2