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 (ORcommon = 1.28, trend Pcomb = 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 (Pcomb<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 Pcomb: 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.
Rheumatoid arthritis (RA), a chronic autoimmune disorder affecting ∼1% of the population, is characterized by immune-cell–mediated destruction of the joint architecture. Gene–environment interactions are thought to underlie RA etiology. Variants within HLA-DRB1 and the hematopoietic-specific phosphatase, PTPN22, are well established RA-susceptibility loci, and although other markers have been identified, they do not fully account for the disease heritability. To identify additional susceptibility alleles, we carried out a multi-tiered, case-control association study genotyping >25,000 putative functional SNPs; here we report our finding of RA-associated variants in chromosome 9q33.2. A detailed genetic analysis of this region, incorporating HapMap information, localizes the RA-susceptibility effects to a 70 kb region that includes a portion of PHF19, all of TRAF1, and the majority of the TRAF1-C5 intergenic region, but excludes the C5 coding region. In addition to providing new insights into underlying mechanism(s) of disease and suggesting novel therapeutic targets, these data provide the underpinnings of a genetic signature that may predict individuals at increased risk for developing RA. Indeed, initial analyses of three known genetic risk factors, HLA, PTPN22, and the chromosome 9q33.2 variants described here, suggest a >45-fold difference in RA risk depending on an individual's three-locus genotype.