DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis.
DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis.
复制标题
DNA甲基化介导抗瓜氨酸肽抗体阳性类风湿性关节炎发展中的基因型和吸烟相互作用
DOI：
10.1186/s13075-017-1276-2
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发表时间：
2017-03-29
影响因子：
4.9
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Meng W;Zhu Z;Jiang X;Too CL;Uebe S;Jagodic M;Kockum I;Murad S;Ferrucci L;Alfredsson L;Zou H;Klareskog L;Feinberg AP;Ekström TJ;Padyukov L;Liu Y
背景多种因素，包括遗传风险和环境风险之间的相互作用，在类风湿关节炎(RA)的易感性中起着重要的作用。然而，其潜在的机制还没有完全被理解。本研究旨在探讨在抗瓜氨酸肽抗体(ACPA)阳性RA的发病过程中，DNA甲基化是否能介导基因与吸烟之间的交互作用。在更大比例的eira(1119名对照和944名ACPA阳性RA患者)和马来西亚类风湿性关节炎流行病学调查(1556名对照和792名ACPA阳性RA患者)中，进一步评估了rs6933349与吸烟之间的相互作用在患ACPA阳性RA的风险中的作用。结果在cg21325723的DNA甲基化中，发现rs6933349与吸烟之间存在显著的基因-环境交互作用。这种基因-吸烟交互作用在高加索人群(乘性P值 = 0.056；加性P值 = 0.016)和亚洲人群(乘性P值 = 0.035；加性P值 = 0.00027)发生ACPA阳性的风险中是一种新的交互作用，它是通过cg21325723基因甲基化介导的。结论cg21325723基因甲基化可以介导rs6933349与吸烟之间的基因-环境交互作用，影响ACPA阳性RA的发病风险，从而成为整合内在遗传和外部环境风险因素的潜在调节因素。
BackgroundMultiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA.MethodsWe investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA). Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA.ResultsWe identified and replicated one significant gene-environment interaction between rs6933349 and smoking in DNA methylation of cg21325723. This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicativePvalue = 0.056; additivePvalue = 0.016) and Asian populations (multiplicativePvalue = 0.035; additivePvalue = 0.00027), and it is mediated through DNA methylation of cg21325723.ConclusionsWe showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors.