Objective: The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analysed.
Methods: A multicentre association study consisting of 4 RA case-control series (4397 cases and 2857 controls) and 3 SLE case-control series (591 cases and 2199 shared controls) was conducted. Genotyping was performed using TaqMan genotyping assay for two single nucleotide polymorphisms (SNPs) that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay.
Results: Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between patients with SLE and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in the present study, while they decreased the risk in the original studies. A significant difference was found between risk allele carriers and non-carriers of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymphoblastoid cell lines (p = 0.04).
Conclusion: Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.
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▸ Additional data (supplementary methods and supplementary table 1) are published online only at http://ard.bmj.com/content/vol69/issue2
KN, YK and KI contributed equally to this work.
Funding This work was supported by grants provided by the Japan Orthopaedics and Traumatology Foundation (KI), Takeda Science Foundation (KI), the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research; KI), (Knowledge Cluster Initiative; HI, MI) and the Japanese Ministry of Health, Labour and Welfare (YK, KY). The IORRA cohort was supported by non-restricted research grants from 36 pharmaceutical companies; Abbott Japan, Asahikasei Kuraray Medical, Asahikasei Pharma, Astellas Pharma, AstraZeneca, Banyu Pharmaceutical, Chugai Pharmaceutical, Daiichi Fine Chemical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, GlaxoSmithKline, Janssen Pharmaceutical, Japan Tobacco, Kaken Pharmaceutical, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Chemical Medience, Mitsubishi Tanabe Pharma, Nippon Chemiphar, Nippon Shinyaku, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Sanofi-Aventis, Santen Pharmaceutical, Sanwa Kagaku Kenkyusho, Sekisui Medical, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Teijin Pharma, Torii Pharmaceutical, Toyama Chemical, UCB Japan, Wyeth and Zeria Pharmaceutical.
Competing interests None.
Ethics approval The study was approved by the local ethics committee of each institute.
Provenance and Peer review Not commissioned; externally peer reviewed.