Abstract
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.
Highlights
Carotid intima-media thickness is defined as a progressive thickening of the arterial wall and is characterized by the presence of large arterial wall deposits
Meta-analysis performed in smokers and non-smokers from Rotterdam Study revealed a stronger association between cg05575921 and Carotid intima-media thickness (cIMT) in smokers, in comparison to non-smokers.Further adjustments for additional potential confounders including body mass index (BMI), HDL cholesterol/triglycerides ratio, systolic blood pressure, antihypertensive and Discovery Panel Beta p value
We report differential DNA methylation at one CpG site and 34 differentially methylated regions (DMRs) as associated with cIMT
Summary
Carotid intima-media thickness (cIMT) is defined as a progressive thickening of the arterial wall and is characterized by the presence of large arterial wall deposits. Evidence suggests that cIMT may be implicated as an intermediate factor in the causal pathway leading to cardiovascular disease [5] and can be used as a predictor of CAD and stroke. Ultrasound of the carotid artery is widely used as a non-invasive procedure to detect the presence of atherosclerotic plaques and as a marker of subclinical vascular disease [6]. A cIMT value above 75th percentile threshold for a person’s age, sex and race in asymptomatic individuals is associated with risk of myocardial infarction, stroke and death from CAD is significantly increased as compared to the average of the population [7]. The addition of cIMT to the Framingham Risk Score has been shown to improve the 10-year risk prediction of myocardial infarction or stroke independent of age, sex
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