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Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

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Portilla-Fernández, Eliana  ORCID logo
Hwang, Shih-Jen 
Wilson, Rory 
Maddock, Jane 
Hill, W David 


Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.


Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi:

Funder: ZonMw; doi:

Funder: Research Institute for Diseases in the Elderly

Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi:

Funder: Health Promotion Administration, Ministry of Health and Welfare; doi:

Funder: Municipality of Rotterdam


Cardiovascular risk factors, Common carotid intima-media thickness, DNA methylation, Differentially methylated regions, Epigenome-wide association studies, Mendelian randomization, Vascular outcomes, Carotid Intima-Media Thickness, Coronary Artery Disease, Cross-Sectional Studies, Epigenome, Humans, Risk Factors

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Eur J Epidemiol

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Springer Science and Business Media LLC
Medical Research Council (MC_UU_12015/2)
MRC (MC_UU_00006/2)