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Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis

Nature Genetics volume 34, pages 395–402 (2003)Cite this article

Abstract

Individuals 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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Figure 1: Gene content of NT_034367.1 in chromosome 1p36, case-control association and linkage disequilibrium.
Figure 2: Structure of PADI4.
Figure 3: Expression of PADI4.
Figure 4: Stability of susceptible and non-susceptible transcripts of PADI4 mRNA measured as degradation rate.

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Acknowledgements

We wish to thank E. Tatsu, K. Kobayashi, M. Mito, N. Iwamoto and the other members of the rheumatoid arthritis team for their advice and technical assistance; H. Kawakami for his expertise in computer programming; and many members of the SNP Research Center for helpful discussions and assistance with various aspects of this study. This work was supported by a grant from the Japanese Millennium Project.

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Authors and Affiliations

  1. Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22, Suehirocho, Tsurumi-ku, Yokohama City, 230-0045, Kanagawa, Japan

    Akari Suzuki, Ryo Yamada, Xiaotian Chang, Shinya Tokuhiro & Kazuhiko Yamamoto

  2. Sankyo, Tokyo, Japan

    Shinya Tokuhiro, Masakatsu Suzuki, Miyuki Nagasaki, Makiko Nakayama-Hamada, Reimi Kawaida, Mitsuru Ono, Masahiko Ohtsuki & Hidehiko Furukawa

  3. Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan

    Tetsuji Sawada & Kazuhiko Yamamoto

  4. Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan

    Shinichi Yoshino

  5. Yukioka Hospital, Osaka, Japan

    Masao Yukioka

  6. National Sagamihara Hospital, Kanagawa, Japan

    Shigeto Tohma

  7. Matsubara Mayflower Hospital, Hyogo, Japan

    Tsukasa Matsubara

  8. Osaka Minami National Hospital, Osaka, Japan

    Shigeyuki Wakitani

  9. Department of Orthopedic Surgery, Tottori University, Tottori, Japan

    Ryota Teshima

  10. Yamanashi Prefectural Central Hospital, Yamanashi, Japan

    Yuichi Nishioka

  11. Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan

    Akihiro Sekine, Aritoshi Iida & Yusuke Nakamura

  12. Laboratory for Medical Informatics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan

    Atsushi Takahashi & Tatsuhiko Tsunoda

  13. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yusuke Nakamura

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Correspondence to Ryo Yamada.

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Suzuki, A., Yamada, R., Chang, X. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34, 395–402 (2003). https://doi.org/10.1038/ng1206

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