Suzuki Akari, Yamada Ryo, Chang Xiaotian, Tokuhiro Shinya, Sawada Tetsuji, Suzuki Masakatsu, Nagasaki Miyuki, Nakayama-Hamada Makiko, Kawaida Reimi, Ono Mitsuru, Ohtsuki Masahiko, Furukawa Hidehiko, Yoshino Shinichi, Yukioka Masao, Tohma Shigeto, Matsubara Tsukasa, Wakitani Shigeyuki, Teshima Ryota, Nishioka Yuichi, Sekine Akihiro, Iida Aritoshi, Takahashi Atsushi, Tsunoda Tatsuhiko, Nakamura Yusuke, Yamamoto Kazuhiko
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.
Nat Genet. 2003 Aug;34(4):395-402. doi: 10.1038/ng1206.
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.
类风湿关节炎患者常常具有针对瓜氨酸化肽的自身抗体，这表明肽基精氨酸脱亚氨酶（由PADI基因编码的瓜氨酸化酶）参与了类风湿关节炎的发病过程。先前的连锁研究表明，类风湿关节炎的一个易感基因座包含四个PADI基因，但并未确定哪个PADI基因赋予了类风湿关节炎易感性。我们采用病例对照连锁不平衡研究表明，4型肽基精氨酸脱亚氨酶（PADI4）是类风湿关节炎的一个易感基因座（P = 0.000008）。PADI4在血液学和类风湿关节炎滑膜组织中表达。我们还鉴定出一种与类风湿关节炎易感性相关的PADI4单倍型，该单倍型影响转录本的稳定性，并与类风湿关节炎患者血清中瓜氨酸化肽抗体水平相关。我们的结果表明，与类风湿关节炎易感性相关的PADI4单倍型增加了作为自身抗原的瓜氨酸化肽的产生，从而导致患该病的风险增加。
