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TRAF1/C5 polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies.

ABSTRACT: INTRODUCTION: Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients. METHODS: 615 RA patients from the Leiden Early Arthritis Clinic (EAC) (mean follow-up 7.6 years) were genotyped for rs10818488. In addition 5634 persons enrolled in the PROspective Study of Pravastatin in the Elderly at Risk (mean follow-up 3.2 years) were genotyped for rs2416808 (R(2) >0.99 with rs10818488). The life/death status was determined and for the deceased persons the cause of death was ascertained. Cox proportional hazards and regression models were used to assess hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Seventy-seven RA patients died. The main death causes in RA patients were cardiovascular diseases (37.7%), cancer (28.6%) and death due to infections (9.1%). No association was observed between the rs10818488 susceptible genotype AA and cardiovascular mortality (HR 1.08 95%CI 0.54 to 2.15) and all-cause mortality (HR 0.81 95%CI 0.27 to 2.43). Similar findings were observed for rs2416808 susceptible genotype GG in the non-RA cohort (HR 0.99; 95%CI 0.79 to 1.25 and HR 0.89; 95%CI 0.64 to 1.25, respectively). CONCLUSIONS: The TRAF1/C5 region is not associated with an increased mortality risk.

SUBMITTER: van Nies JA

PROVIDER: S-EPMC2888185 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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TRAF1/C5 polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies.

van Nies Jessica A B JA Marques Rute B RB Trompet Stella S de Jong Zuzana Z Kurreeman Fina A S FA Toes Rene E M RE Jukema J Wouter JW Huizinga Tom W J TW van der Helm-van Mil Annette H M AH

Arthritis research & therapy 20100305 2

<h4>Introduction</h4>Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As ...[more]

PMID: 20205706

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Project description: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 < 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).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.

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TRAF1/C5 polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies.

Publications

TRAF1/C5 polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies.

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