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

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% o...

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Published in:	PLoS medicine 2007-09, Vol.4 (9), p.e278-e278
Main Authors:	Kurreeman, Fina A S, Padyukov, Leonid, Marques, Rute B, Schrodi, Steven J, Seddighzadeh, Maria, Stoeken-Rijsbergen, Gerrie, van der Helm-van Mil, Annette H M, Allaart, Cornelia F, Verduyn, Willem, Houwing-Duistermaat, Jeanine, Alfredsson, Lars, Begovich, Ann B, Klareskog, Lars, Huizinga, Tom W J, Toes, Rene E M
Format:	Article
Language:	eng
Subjects:	Arthritis, Rheumatoid - epidemiology Arthritis, Rheumatoid - genetics Case-Control Studies Complement C5 - genetics Genetic aspects Genetic Linkage - genetics Genetic Predisposition to Disease Genetic Variation - genetics Genetics Genetics and Genomics Histocompatibility antigens HLA histocompatibility antigens Humans Identification and classification Medicin och hälsovetenskap Polymorphism, Single Nucleotide - genetics Rheumatoid Arthritis Rheumatology Risk Factors Severity of Illness Index TNF Receptor-Associated Factor 1 - genetics
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Summary:	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. 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). 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.
ISSN:	1549-1676 1549-1277 1549-1676