Abstract
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. 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. 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. 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. 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).
Highlights
Coronary heart disease (CHD) is one of the leading causes of morbidity and mortality worldwide.[1]
Baseline DNA methylation was measured for 494 coronary heart disease (CHD) cases, whose CHD occurred during the follow-up period until 31 December 2015, and 494 matched controls
Baseline DNA methylation was measured for 494 CHD cases and 494 matched controls
Summary
Coronary heart disease (CHD) is one of the leading causes of morbidity and mortality worldwide.[1]. Methylation at cytosine-phosphate-guanine (CpG) dinucleotides is a common epigenetic modification of DNA,[3] which forms an interface between the genotype and the environment.[4] DNA methylation are responsive to environmental stimuli and unhealthy lifestyles, including smoking,[5] alcohol consumption,[6] and obesity.[7] This makes DNA methylation a potential biomarker of environmental-related and lifestyle-driven diseases of adulthood, for example, metabolic dysfunction (including hypertension,[8] diabetes,[9] and atherogenic dyslipidemia[10]). Investigating the environmentally responsive DNA methylation change linked to CHD could gain insights into the underlying mechanisms and identify novel clinical biomarkers and therapeutic targets of CHD. 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
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