Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study

eLife

Junshi Chen¹  Yu Guo²  Zhengming Chen³  Dianjianyi Sun⁴  Songchun Yang⁴  Liming Li⁴  Canqing Yu⁴  Jiahui Si⁵  Jun Lv⁶  Wei Chen⁷  Yifen Lin⁸  Liming Liang⁹  Ling Yang^1,10  Yiping Chen^1,10  Robin G Walters^1,10  Iona Y Millwood^1,10  Huaidong Du^1,10  Yujie Hua^1,11  Jingchao Liu^1,12 

[1] China National Center for Food Safety Risk Assessment, Beijing, China;Chinese Academy of Medical Sciences, Beijing, China;Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom;Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China;Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China;Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, United States;Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China;Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education, Beijing, China;Peking University Institute of Environmental Medicine, Beijing, China;Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, United States;Department of Urology, West China Hospital, Sichuan University, Chengdu, China;Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, United States;Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, United Kingdom;Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom;NCDs Prevention and Control Department, Suzhou CDC, Jiangsu, China;NCDs Prevention and Control Department, Wuzhong CDC, Jiangsu, China;

关键词: coronary heart disease;    epigenetics;    DNA methylation;    epidemiology;    Human;   

DOI  :  10.7554/eLife.68671

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Background:Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population.Methods:We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10 year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module.Results:After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR < 0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47 % decrease to a 118 % increase. Mediation analyses revealed 28.5 % of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of ANKS1A gene (P for mediation effect = 0.036). Methylation level at the promoter region of SNX30 was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7 % (P = 0.003) via systolic blood pressure and 6.4 % (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD.Conclusions:We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and blood pressure-related pathways to CHD risk.Funding:This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).

【 授权许可】

CC BY