Vol.22 No.1

Original Article

A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations

Authors

Roubila Meziani1,2,3 , Ryo Yamada4 , Meiko Takahashi4 , Kenei Ohigashi4 , Akio Morinobu5 , Chikashi Terao4,6 , Hitomi Hiratani1,4 , Koichiro Ohmura6 , Masao Yamaguchi1,4 , Takashi Nomura7 , Alexandre Vasilescu4,8 , Miki Kokubo1,4, Victor Renault1,4, Katsura Hirosawa1,4, Chanavee Ratanajaraya4, Simon Heath2, Tsuneyo Mimori6, Shimon Sakaguchi7, Mark Lathrop2,3, Inga Melchers9, Shunichi Kumagai5, Fumihiko Matsuda1,2,4,8

  • CREST Program, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan
  • Centre National de Genotypage, Institute Genomique, Commissariat a l’Energie Atomique, 91057, Evry, France
  • Fondation Jean Dausset-CEPH, 75010, Paris, France
  • Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Yoshida, Kyoto, 606-8501, Japan
  • Department of Clinical Pathology and Immunology, Graduate School of Medicine, Kobe University, Kobe, 650-0017, Japan
  • Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
  • Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
  • Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University, Kyoto, 606-8501, Japan
  • Clinical Research Unit for Rheumatology, Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, 79106, Freiburg, Germany
Received:

28 February 2011

Accepted:

22 April 2011

Published online:

24 May 2011

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Abstract

Rheumatoid arthritis (RA) is a common systemic autoimmune disease and its onset and prognosis are controlled by genetic, immunological, and environmental factors. The HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. However, they cover only a part of its genetic components and their relative contribution is different between populations. To identify novel genetic determinants, we took a candidate gene approach in a trans-ethnic manner. After critical selection of 169 genes based on their immunological function, we performed SNP discovery of these genes by the resequencing of exons and surrounding areas using European and Japanese DNAs. We then generated a panel of 1,509 SNPs for case-control association study in both populations. The DerSimonian-Laird test for metaanalysis, using the combined results of the two populations, identified rs7551957 at the 50-flanking region of the lowaffinity Fc-gamma receptor IIa (FCGR2A) gene as the strongest candidate for the association (p = 8.6 × 10-5, odds ratio = 1.58 with 95%CI 1.25?1.99). Suggestive signals were also obtained for three SNPs in the dihydropyrimidine dehydrogenase (DPYD) gene (rs6685859; p = 1.3 × 10-4, rs7550959; p = 1.5 × 10-4 and rs7531138; p = 1.7 × 10-4) and an intronic SNP, rs2269310, of the erythrocytic spectrin beta (SPTB) gene (p = 7.9 × 10-4).

Key words

FCGR2A - Genotyping - Rheumatoid arthritis - Single nucleotide polymorphism - Trans-ethnic study