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
Songchun Yang
Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
Dianjianyi Sun
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
Yu Guo
Chinese Academy of Medical Sciences, Beijing, China
Yifei Lin
Department of Urology, West China Hospital, Sichuan University, Chengdu, China
Iona Y Millwood
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
Robin G Walters
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
Ling Yang
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
Yiping Chen
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
Huaidong Du
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
Yujie Hua
NCDs Prevention and Control Department, Suzhou CDC, Jiangsu, China
Jingchao Liu
NCDs Prevention and Control Department, Wuzhong CDC, Jiangsu, China
Junshi Chen
China National Center for Food Safety Risk Assessment, Beijing, China
Zhengming Chen
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Wei Chen
Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, 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
Liming Liang
Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, United States
Liming Li
Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
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).
