A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis

Background Rheumatoid arthritis ( RA) is a chronic autoimmune disorder affecting; similar to 1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens ( HLAs) account for; similar to 30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 ( C5) and/or TNF receptor-associated factor 1 ( TRAF1), located on Chromosome 9q33-34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA. Methods and Findings We performed a multitiered case-control study using 40 single-nucleotide polymorphisms ( SNPs) from the TRAF1 and C5 ( TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants ( controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (n(cases/controls) 454/ 270), Sweden (n(cases/controls) 1,500/ 1,000) and US (n(cases/controls) 475/475). We observed a significant association ( p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3' end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located similar to 10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls ( odds ratio(common) = 1.28, 95% confidence interval 1.17-1.39, p(combined) = 1.40 x 10(-8)) with a population-attributable risk of 6.1%. The A ( minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients ( p = 0.008). Conclusions Using a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.