Nature Genetics
34, 395 - 402 (2003)
Published online: 29 June 2003; | doi:10.1038/ng1206
Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritisAkari Suzuki1, Ryo Yamada1, Xiaotian Chang1, Shinya Tokuhiro1, 2, Tetsuji Sawada3, Masakatsu Suzuki2, Miyuki Nagasaki2, Makiko Nakayama-Hamada2, Reimi Kawaida2, Mitsuru Ono2, Masahiko Ohtsuki2, Hidehiko Furukawa2, Shinichi Yoshino4, Masao Yukioka5, Shigeto Tohma6, Tsukasa Matsubara7, Shigeyuki Wakitani8, Ryota Teshima9, Yuichi Nishioka10, Akihiro Sekine11, Aritoshi Iida11, Atsushi Takahashi12, Tatsuhiko Tsunoda12, Yusuke Nakamura11, 13
& Kazuhiko Yamamoto1, 31
Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22, Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan. 2
Sankyo, Tokyo, Japan. 3
Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. 4
Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan. 5
Yukioka Hospital, Osaka, Japan. 6
National Sagamihara Hospital, Kanagawa, Japan. 7
Matsubara Mayflower Hospital, Hyogo, Japan. 8
Osaka Minami National Hospital, Osaka, Japan. 9
Department of Orthopedic Surgery, Tottori University, Tottori, Japan. 10
Yamanashi Prefectural Central Hospital, Yamanashi, Japan. 11
Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan. 12
Laboratory for Medical Informatics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan. 13
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Correspondence should be addressed to Ryo Yamada ryamada@src.riken.go.jpIndividuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.
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