Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis
Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis
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DOI：
10.1038/ng1206
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发表时间：
2003-08-01
期刊：
影响因子：
30.8
通讯作者：
Yamamoto, K
中科院分区：
文献类型：
--
作者：
Suzuki, A;Yamada, R;Yamamoto, K
类风湿性关节炎患者经常出现抗瓜氨酸肽的自身抗体，这表明肽基精氨酸脱亚胺酶瓜氨酸酶（由PADI基因编码）参与类风湿性关节炎。先前的连锁研究表明，类风湿性关节炎的易感基因座包括四个PADI基因，但没有确定哪一个PADI基因赋予类风湿性关节炎的易感性。我们使用病例对照连锁不平衡研究表明，PADI 4型是类风湿关节炎的易感基因（P = 0.000008）。PADI 4在血液和类风湿关节炎滑膜组织中表达。我们还确定了与类风湿性关节炎易感性相关的PADI 4单倍型，该单倍型影响转录物的稳定性，并与类风湿性关节炎患者血清中瓜氨酸肽抗体水平相关。我们的研究结果表明，与类风湿性关节炎易感性相关的PADI 4单倍型增加了作为自身抗原的瓜氨酸肽的产生，导致发生疾病的风险增加。
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.