Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting 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 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 9q3334, 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 (ncases/controls 454/270), Sweden (ncases/controls 1,500/1,000) and US (ncases/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 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 ratiocommon 1.28, 95 confidence interval 1.171.39, pcombined 1.40 108) 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).
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.