Acetylsalicylic acid, aging and coronary artery disease are associated with ABCA1 DNA methylation in men

Abstract

BackgroundPrevious studies have suggested that DNA methylation contributes to coronary artery disease (CAD) risk variability. DNA hypermethylation at the ATP-binding cassette transporter A1 (ABCA1) gene, an important modulator of high-density lipoprotein cholesterol and reverse cholesterol transport, has been previously associated with plasma lipid levels, aging and CAD, but the association with CAD has yet to be replicated.ResultsABCA1 DNA methylation levels were measured in leucocytes of 88 men using bis-pyrosequencing. We first showed that DNA methylation at the ABCA1 gene promoter locus is associated with aging and CAD occurrence in men (P < 0.05). The latter association is stronger among older men with CAD (≥61 years old; n = 19), who showed at least 4.7% higher ABCA1 DNA methylation levels as compared to younger men with CAD (<61 years old; n = 19) or men without CAD (n = 50; P < 0.001). Higher ABCA1 DNA methylation levels in older men were also associated with higher total cholesterol (r = 0.34, P = 0.03), low-density lipoprotein cholesterol (r = 0.32, P = 0.04) and triglyceride levels (r = 0.26, P = 0.09). Furthermore, we showed that acetylsalicylic acid therapy is associated with 3.6% lower ABCA1 DNA methylation levels (P = 0.006), independent of aging and CAD status of patients.ConclusionsThis study provides new evidence that the ABCA1 epigenetic profile is associated with CAD and aging, and highlights that epigenetic modifications might be a significant molecular mechanism involved in the pathophysiological processes associated with CAD. Acetylsalicylic acid treatment for CAD prevention might involve epigenetic mechanisms.

Association between DNA methylation and coronary heart disease or other atherosclerotic events: A systematic review

“…In total, 51 articles met our eligibility criteria (Supplementary Table 1) and were included in the analysis. Of the 51 selected studies, 17 included participants from Europe [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] 14 from China [23][24][25][26][27][28][29][30][31][32][33][34][35][36], six from USA [37][38][39][40][41][42], three from India [43][44][45], two from Canada [46,47], and one each from Japan [48], Malaysia [49], Iran [50], Russia [51], Brazil [52] and Mexico [53]…”

“…Seven studies analyzed global DNA methylation [6,7,23,34,36,42,52], 31 followed a candidate-gene approach [8][9][10][11][12][13][14]20,22,[24][25][26][27][28][29][30][31][32][33]35,[38][39][40][41]45,46,49,50,[54][55][56], seven were epigenome-wide association studies (EWAS) [16,18,19,21,44,48,53], two used both global DNA methylation and candidate-gene approaches [37,43], three used EWAS and global DNA methylation approaches [15,17,51], and on...…”

“…The vast majority of the selected candidate-gene methylation studies analyzed blood samples (n=28) [8][9][10][11][12]14,20,22,[24][25][26][27][28][29][30][31][32]35,40,41,43,46,47,49,50,56]. The other tissues isolated were aortic [37,39,55] or other vascular tissues [13,38,54] (Supplementary Table 2b).…”

Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

“…Reduction of ABCA1 expression was also observed in peripheral blood mononuclear cells in aging adult (67–87 years old) compared to young adult (25–34 years old) human donors [88]. DNA methylation at the ABCA1 promoter has been shown to negatively correlate with HDL levels and incidence of coronary artery disease (CAD) in individuals with familial hypercholesterolemia, and ABCA1 promoter methylation levels have been shown to increase with age [89, 90]. The accumulation of DNA methylation at the ABCA1 promoter with age may account for the reduction of ABCA1 expression observed by Sene et al in older adults, which would potentially contribute to both increased risk of AMD and CAD in aging individuals.…”

Association of four CpG-SNPs in the vascular-related genes with coronary heart disease

“…Aberrant DNA methylation in promoters has been extensively studied for the pathogenesis of CHD [20][21][22][23]. Genetic variants at CpGs (CpG-SNPs) have been shown to be associated with many human diseases, such as neuropsychiatric disease [24], breast cancer [25], type 2 diabetes [26] and epithelial ovarian cancer [27].…”