PLoS Medicine (Sep 2007)

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

  • Fina A S Kurreeman,
  • Leonid Padyukov,
  • Rute B Marques,
  • Steven J Schrodi,
  • Maria Seddighzadeh,
  • Gerrie Stoeken-Rijsbergen,
  • Annette H M van der Helm-van Mil,
  • Cornelia F Allaart,
  • Willem Verduyn,
  • Jeanine Houwing-Duistermaat,
  • Lars Alfredsson,
  • Ann B Begovich,
  • Lars Klareskog,
  • Tom W J Huizinga,
  • Rene E M Toes

DOI
https://doi.org/10.1371/journal.pmed.0040278
Journal volume & issue
Vol. 4, no. 9
p. e278

Abstract

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BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder affecting approximately 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 approximately 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 findingsWe 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 ConclusionsUsing 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.