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 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.


RESULTS
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.
Kurreeman
Fina A S
FA
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
Padyukov
Leonid
L
Marques
Rute B
RB
Schrodi
Steven J
SJ
Seddighzadeh
Maria
M
Stoeken-Rijsbergen
Gerrie
G
van der Helm-van Mil
Annette H M
AH
Allaart
Cornelia F
CF
Verduyn
Willem
W
Houwing-Duistermaat
Jeanine
J
Alfredsson
Lars
L
Begovich
Ann B
AB
Klareskog
Lars
L
Huizinga
Tom W J
TW
Toes
Rene E M
RE
D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D003182:Complement C5 / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012720:Severity of Illness Index; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics*
D003182:Complement C5; D047990:TNF Receptor-Associated Factor 1