A group of international researchers has performed the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population. Their findings were published in Epidemiology and Global Health, Genetics and Genomics.
Coronary Heart Disease and DNA methylation
Coronary heart disease (CHD) is a major contributor to global mortality and morbidity. In total, an estimated 3.8 million men and 3.4 million women die each year from CHD. Despite progress being made in preventing CHD, more targeted approaches are needed to further reduce CHD incidence. As a result, researchers are exploring other mechanisms, such as DNA methylation, to help prevent the disease.
Methylation of DNA at cytosine-phosphate-guanine (GpG) dinucleotides is a stable epigenetic regulatory mechanism. DNA methylation at CpG sites is dependent on both environmental factors and genetic variation.
In vitro and animal-based studies have shown that DNA methylation changes are involved in the development of CHD. Moreover, large-scale population studies have provided evidence that risk factors for CHD, such as smoking, obesity and hypertension, are linked to persistent differences in leukocyte DNA methylation. Therefore, researchers hope that identifying environmentally responsive genetic loci where DNA methylation is associated with CHD may reveal novel pathways or therapeutic targets for CHD.
Epigenome-wide analysis
In this study, the researchers carried out the first prospective epigenome-wide analysis of DNA methylation in incident CHD in the Asian population. The team conducted a nested case-control study comprising incident CHD cases and matched controls. Methylation levels of baseline blood leukocyte DNA were also measured. Following that, the team performed single CpG site association analysis and network approaches to identify CHD-associated CpG sites and co-methylation gene modules.
Results of epigenome-wide analysis of DNA methylation sites
In total, 982 patients were included in the study, with an average age of 50.1 years. It was found that methylation levels at 25 CpG sites across the genome were associated with incident CHD. The team noted that an increase in levels of methylation of identified CpGs was associated with differences in CHD risk. These differences ranged from a 47% decrease to a 118% increase.
To assess the effect of environmental factors, such as smoking and blood pressure, on DNA methylation and CHD risk, the researchers carried out mediation analyses. Researchers typically employ mediation analyses to understand a known relationship by exploring the underlying mechanisms or process by which one variable influences another through a mediator variable. These analyses revealed that 28.5% of the increased CHD risk associated with smoking was mediated by methylation levels at the promoter region of the ANKS1A gene. Additionally, methylation levels at the promoter region of SNX30 were associated with increased blood pressure and subsequent risk of CHD.
Summary
The researcher’s epigenome-wide analysis has uncovered novel blood methylation alterations associated with incident CHD in the Asian population. Their work has also provided evidence of the possible epigenetic regulations associated with smoking- and blood pressure-related pathways on CHD risk. It is hoped that their work will reveal therapeutic targets that could be used to prevent CHD.
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