Abstract
BackgroundEpigenome-wide association studies using DNA methylation have the potential to uncover novel biomarkers and mechanisms of cardiovascular disease (CVD) risk. However, the direction of causation for these associations is not always clear, and investigations to-date have often failed to replicate at the level of individual loci.MethodsHere, we undertook module- and region-based DNA methylation analyses of incident CVD in the Women’s Health Initiative (WHI) and Framingham Heart Study Offspring Cohort (FHS) in order to find more robust epigenetic biomarkers for cardiovascular risk. We applied weighted gene correlation network analysis (WGCNA) and the Comb-p algorithm to find methylation modules and regions associated with incident CVD in the WHI dataset.ResultsWe discovered two modules whose activation correlated with CVD risk and replicated across cohorts. One of these modules was enriched for development-related processes and overlaps strongly with epigenetic aging sites. For the other, we showed preliminary evidence for monocyte-specific effects and statistical links to cumulative exposure to traditional cardiovascular risk factors. Additionally, we found three regions (associated with the genes SLC9A1, SLC1A5, and TNRC6C) whose methylation associates with CVD risk.ConclusionsIn sum, we present several epigenetic associations with incident CVD which reveal disease mechanisms related to development and monocyte biology. Furthermore, we show that epigenetic modules may act as a molecular readout of cumulative cardiovascular risk factor exposure, with implications for the improvement of clinical risk prediction.
Highlights
Epigenome-wide association studies using DNA methylation have the potential to uncover novel biomarkers and mechanisms of cardiovascular disease (CVD) risk
In order to improve statistical power, we focused on differentially methylated regions (DMRs) with respect to incident CVD status
The modules and regions discovered in this investigation provide insights into the complex relationships between DNA methylation and cardiovascular disease risk
Summary
We undertook module- and region-based DNA methylation analyses of incident CVD in the Women’s Health Initiative (WHI) and Framingham Heart Study Offspring Cohort (FHS) in order to find more robust epigenetic biomarkers for cardiovascular risk. Blood samples used for measurement of DNA methylation and clinical biochemistry were taken at Exam 1. Data for the validation set came from a substudy of the Framingham Heart Study that measured DNA methylation in 2726 subjects from the Offspring Cohort. Fasting blood samples for both methylation and clinical biochemistry were collected from participants at Exam 8, which took place from 2005-8. Blood samples were provided for clinical biochemistry measurements in previous exams, constituting the “past exposures” examined here. Adjudicated cardiovascular event data was collected through 2015, and events were defined here as any of MI, angina pectoris, stroke (approximately 90% being ischemic), or death from CHD (Framingham event codes 1–29)
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