Digna Cabral

Background: Carotid intima‐media thickness (IMT) is a measure of atherosclerosis and a predictor of vascular diseases. Traditional vascular risk factors and genetic variants do not completely explain the variation in carotid IMT. We sought to identify epigenetic factors that may contribute to the remaining carotid IMT variability. Methods and Results: An epigenome‐wide association study was performed in 61 Dominican families with 769 individuals. A cytosine nucleotide that precedes a guanine nucleotide methylation in blood‐derived DNA was measured using the Human MethylationEPIC BeadChip. Linear mixed model analyses were performed regressing bifurcation carotid IMT (bIMT) on beta values for cytosine nucleotide that precedes a guanine nucleotide sites, adjusting for covariates, followed by differentially methylated region (DMR) analysis. One‐sample Mendelian randomization analysis was conducted to investigate causal associations between DMRs and bIMT. Twenty‐five DMRs were associated with bIMT (Sidak P P =2.45×10 ⁻¹⁷ ) overlapping with the promoter of PM20D1 . All 11 cytosine nucleotides that precede a guanine nucleotide within the PM20D1 DMR were positively associated with bIMT ( P =0.0007–0.00006). Methylation of the PM20D1 DMR was associated with cis variants, including rs823154 (β=0.26; P =1.1×10 ⁻¹²¹ ). As reported in GTEx (Genotype‐Tissue Expression project), rs823154 is an expression quantitative trait locus for PM20D1 in multiple tissues, including the aorta ( P =2.3×10 ⁻⁶⁰ ) and blood ( P =4.0×10 ⁻⁷³ ), suggesting that hypermethylation of the PM20D1 DMR directs lower expression of the gene. Mendelian randomization analysis supported a causal role for PM20D1 DMR in bIMT ( P =0.049). Conclusions: Our study and previous expression quantitative trait locus studies provide converging evidence that reduced PM20D1 expression via hypermethylation of the promoter is associated with increased atherosclerosis.

Background and purpose: Carotid plaque (CP), carotid intima media thickness (cIMT), and stiffness (STIFF) are pre-clinical markers of atherosclerosis and predictors of cerebrovascular disease (CVD). We sought to investigate whether STIFF is a significant determinant of cIMT and CP, which may provide an insight into the mechanism by which STIFF adds to the risk of CVD. Methods: We analyzed 876 stroke-free subjects from the Northern Manhattan Study with available ultrasound measures. To obtain the associations with STIFF, we performed multivariable-adjusted regression, negative binomial regression (for CP number), and multinomial logistic regression (for plaque area). Results: The mean age was 64 ± 9 years; 63% women and 65% Caribbean Hispanics. The mean cIMT was 0.93 ± 0.9 mm, the mean diastolic diameter 6.24 ± 0.94 mm, and STIFF 8.6 ± 6.2 ln mmHg. Prevalence of CP was 57%, and the mean total plaque area was 22.6 ± 23.0 mm². STIFF was positively associated with cIMT but not with CP. There was an association between diastolic diameter and thick plaque. For each millimeter increase in diastolic diameter, there was about a 20% increased risk of having thick plaque (vs. no plaque). In longitudinal analyses, each millimeter increase in diastolic diameter was associated with a 37% increased risk of incident plaque. Conclusion: Increased STIFF was associated with increased cIMT and carotid artery dilatation with greater plaque burden. Increased cIMT and plaque burden represent vascular remodeling likely resulting from the two different age-related mechanisms, one that includes diffuse wall thickening (cIMT) with STIFF and another that incorporates focal atherosclerosis (plaque) with luminal dilatation.

Objectives: The presence of atherosclerotic plaque in the carotid arteries is a strong predictor of cardiovascular disease (CVD). Research and data on CVD risk have been derived primarily from individuals aged 55 years or older, and assessment of CVD risk among young and middle-aged adults seldom has been studied. The use of ultrasonography to measure carotid intima-media thickness (IMT) and...