Historically, a major focus of this project has been the identification of rheumatoid arthritis susceptibility genes. The GGB was one of the founding members of the North American Rheumatoid Arthritis Consortium (NARAC), which has collected large numbers of DNA samples from sibling pairs concordant for rheumatoid arthritis as well as singleton cases. During the 2007 reporting period we discovered a variant of STAT4 (which encodes the signal transducer and activator of transcription 4 protein) that is associated with both rheumatoid arthritis and systemic lupus erythematosus. We also discovered a single nucleotide polymorphism close to the C5 and TRAF1 loci that is associated with rheumatoid arthritis. Our contributions to large case-control genetic association studies are continuing to help reveal the genetic factors that contribute to susceptibility to rheumatoid arthritis. We attempted to replicate association of a chromosome 7q variant recently reported in female, but not in male rheumatoid arthritis patients from the United Kingdom. We genotyped the reported SNP and 16 additional tag SNPs from the chromosomal region in a total of 1,605 cases and 2,640 controls used in the North American Rheumatoid Arthritis Consortium (NARAC) studies. We failed to find statistically robust evidence for association of the reported variant or any of the tag SNPs in the NARAC study collection, even in an analysis limited to females (Korman et al, 2009). Large, well-powered replication studies, such as this one, allow the recognition of whether reported associations do or do not rise to a level warranting further investigations, such as functional studies of the genetic variants. By combining the results of two large genome-wide association studies for rheumatoid arthritis susceptibility (with a combined 3393 cases and 12,462 controls), we identified several potential new disease-susceptibility loci. We attempted to confirm the association of the new variants by genotyping them in an independent collection of 3929 rheumatoid arthritis cases and 5807 controls. One of the new variants located in the CD40 gene, was associated with disease in the replication collection and reached genome-wide significance (P <5 x 10-8) in the combined analysis. Five more of the new variants were associated with disease in the replication collection and although they exhibited good association (P <1 x 10-6), did not reach genome-wide significance. These variants were in KIF5A/PIP4K2C, MMEL1/TNFRSF14, CCL21, PRKCQ. The results of this study combined with previously identified susceptibility alleles in TRAF1/C5, TNFAIP3, highlight the role of the CD40 signaling pathway and the downstream NFKappaB pathway in the pathogenesis of rheumatoid arthritis (Raychauduri et al, 2008). We previously reported that the STAT4 variant we originally identified as associated with rheumatoid arthritis in a North American case-control collection was also associated with rheumatoid arthritis in a large Korean case-control collection. We hypothesized that other genetic variants with robust evidence for association with rheumatoid arthritis in Caucasians would also contribute to disease in the Korean population. We tested rheumatoid arthritis-associated variants in TRAF1/C5, TNFAIP3, IL2/IL21, CD40, and CCL21 in 1128 patients and 1022 controls from Korea. Interestingly, the R620W variant of PTPN22, which is associated with a variety of autoimmune diseases in different Caucasian populations, is not present in the Korean population. We therefore identified tag SNPs and novel variants in this important gene and genotyped them in the same Korean case-control collection. The disease-associated SNPs in TNFAIP3 and IL2/IL21 were not polymorphic in the Korean population and the TRAF1/C5, CD40 and CCL21 variants were not associated with rheumatoid arthritis in the Korean population. We confirmed, however, strong association of a genetic variant in PADI4 that was previously reported in Asian populations, but which has only modest evidence for association in Caucasians. This well-powered study suggests that the genetic factors that contribute to rheumatoid arthritis susceptibility are for the most part distinct in Caucasian and Asian patients (Lee et al, 2009). With the NARAC and Canadian collaborators, we performed a new genome-wide association study of a new collection of 2418 Caucasian rheumatoid arthritis cases and 4504 Caucasian controls and identified a variant in the REL gene as a new susceptibility locus. This association replicated in an independent collection of 2,604 cases and 2,882 controls. When all the data (the original NARAC collection GWAS, this new NARAC and Canadian GWAS, and the data from this new replication collection) were combined, the allelic association P value of 3.08 x 10-14 greatly surpassed the threshold for genome-wide significance. The REL gene encodes c-REL, a member of the NFKappaB transcription factors. These data further support the role of the NFKappB pathway in the pathogenesis of rheumatoid arthritis. The combined data also provided definitive support for variants located within two genes, CTLA4 (a gene encoding a T-cell inhibitory protein with prior evidence of association with rheumatoid arthritis) and BLK (a gene encoding B lymphoid tyrosine kinase that has been associated with SLE) (Gregersen et al, 2009).
