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

Authors

Konstanze Tan, Sarah E Harris, Jane Maddock, Darwin Tay, Pritesh R Jain, HELIOS Study Team, Shi Qi Mok, Maxime Herbrard, Ulf Schminke, Can Can Xue, Liuh Ling Goh, Theresia Mina, Alexander Teumer, Weng Khong Lim, Khai Pang Leong, Khung Keong Yeo, Ching-Yu Cheng, Xueling Sim, Lee Eng Sing, Joanna M Wardlaw, Henry Völzke, Andrew Wong, Simon R Cox, Rinkoo Dalan, Abbas Dehghan, Marie Loh
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Abstract

medRxiv [Preprint]. 2025 Nov 23:2025.11.21.25340774. doi: 10.1101/2025.11.21.25340774.

ABSTRACT

BACKGROUND: Carotid-intima media-thickness predicts cardiovascular events and informs mechanistic research on cardiovascular diseases (CVD). However, CVD research remains Eurocentric despite etiological differences across ancestries. Incorporating Asian populations- who face substantial CVD burden with distinct etiological landscape- can enhance our understanding of cIMT biology and subclinical processes linked to CVD. This study aimed 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.

METHODS: 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, CVD 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).

RESULTS: 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).

CONCLUSIONS: 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 CAD risk via NBEAL2 regulation, nominating biologically relevant targets while underscoring the need for larger multi-omics resources to refine mechanisms.

PMID:41334702 | PMC:PMC12668099 | DOI:10.1101/2025.11.21.25340774