Epigenome-Wide Association Study in Asian Cohort Identifies Novel DNA Methylation Markers for Carotid Intima-Media Thickness

TL;DR

This study finds new DNA methylation markers linked to carotid intima-media thickness in an Asian population, suggesting potential roles in cardiovascular disease risk.

Contribution

The study identifies three novel DNA methylation markers for cIMT in an Asian cohort and links them to coronary artery disease risk via NBEAL2.

Findings

Three novel CpG-cIMT associations were identified with strong statistical significance.

Methylation at cg08227773 is causally linked to coronary artery disease and NBEAL2 gene expression.

A methylation risk score based on three CpGs is associated with elevated cIMT above clinical risk thresholds.

Abstract

Carotid-intima media-thickness (cIMT) predicts cardiovascular events and informs mechanistic research on cardiovascular diseases. However, cardiovascular disease research remains Eurocentric despite etiological differences across ancestries. Incorporating Asian populations who face substantial cardiovascular disease burden with distinct etiological landscape can enhance our understanding of cIMT biology and subclinical processes linked to CVD. This study aims to elucidate methylation-based mechanisms of cIMT through DNA methylation profiling integrated with multi-omics data and clinically informative cIMT thresholds, leveraging an Asian cohort to enhance discovery.

We conducted an epigenome-wide association study (EWAS) of cIMT using peripheral blood DNA methylation at ~850,000 CpG sites in the Asian Health for Life in Singapore (HELIOS) cohort (n=1,357), followed by targeted trans-ancestry meta-analysis with European cohorts (overall n=2,765). Causal inference analyses (summary data-based Mendelian Randomisation [SMR] and colocalisation) evaluated methylation-mediated effects on cIMT, cardiovascular disease and proximal gene expression. We derived a methylation risk score (MRS) and tested its association with cIMT thresholds indicative of elevated cardiovascular risk (≥75th percentile for age, sex and ethnicity).

Three novel CpG-cIMT associations were identified (P<9.35E-07). Causal analyses supported cg08227773 methylation-mediated effects on both coronary artery disease risk (PSMR=2.91E-05, coloc PP.H4 =0.91) and NBEAL2 (Neurobeachin-like 2) expression (PSMR=9.13E-08, coloc PP.H4=0.69), a gene implicated in immune dysregulation. MRS of cIMT aggregating the three sentinel CpGs was associated with clinically-informative cIMT elevation (Odds Ratio=2.75 for Q4 vs Q1, 95% CI: 1.47–5.13).

Through Asian-led discovery, this study identifies three novel DNA methylation markers for cIMT that are linked to cIMT elevation above clinically meaningful risk thresholds. Causal inference analyses suggest methylation-mediated coronary artery disease risk via NBEAL2 regulation, nominating biologically relevant targets while underscoring the need for larger multi-omics resources to refine mechanisms.

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