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

Abstract

BACKGROUND:

Rheumatoid 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 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 approximately 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 1.17-1.39, pcombined = 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.

• Authors: 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
• Journal: PLoS medicine (PLoS Med) Vol. 4 Issue 9 Pg. e278 (Sep 2007) ISSN: 1549-1676 [Electronic] United States
• PMID: 17880261 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Complement C5
• TNF Receptor-Associated Factor 1

Topics

• Arthritis, Rheumatoid (epidemiology, genetics)
• Case-Control Studies
• Complement C5 (genetics)
• Genetic Linkage (genetics)
• Genetic Predisposition to Disease
• Genetic Variation (genetics)
• Humans
• Polymorphism, Single Nucleotide (genetics)
• Risk Factors
• Severity of Illness Index
• TNF Receptor-Associated Factor 1 (genetics)