Dueker Nicole D, Zhao Hongyu, Gardener Hannah, Kaur Sonya S, Dong Chuanhui, Cabral Digna, Sacco Ralph L, Blanton Susan H, Rundek Tatjana, Wang Liyong
John P. Hussman Institute for Human Genomics, University of Miami Miami FL USA.
Department of Biostatistics Yale School of Public Health New Haven CT USA.
J Am Heart Assoc. 2025 Jan 21;14(2):e034033. doi: 10.1161/JAHA.123.034033. Epub 2025 Jan 10.
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.
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 <0.05), with the strongest DMR (Sidak =2.45×10) overlapping with the promoter of . All 11 cytosine nucleotides that precede a guanine nucleotide within the DMR were positively associated with bIMT (=0.0007-0.00006). Methylation of the DMR was associated with variants, including rs823154 (β=0.26; =1.1×10). As reported in GTEx (Genotype-Tissue Expression project), rs823154 is an expression quantitative trait locus for in multiple tissues, including the aorta (=2.3×10) and blood (=4.0×10), suggesting that hypermethylation of the DMR directs lower expression of the gene. Mendelian randomization analysis supported a causal role for DMR in bIMT (=0.049).
Our study and previous expression quantitative trait locus studies provide converging evidence that reduced expression via hypermethylation of the promoter is associated with increased atherosclerosis.
颈动脉内膜中层厚度（IMT）是动脉粥样硬化的一项指标，也是血管疾病的预测因子。传统的血管危险因素和基因变异并不能完全解释颈动脉IMT的变异性。我们试图确定可能导致剩余颈动脉IMT变异性的表观遗传因素。
对61个多米尼加家庭的769名个体进行了全表观基因组关联研究。使用人类甲基化EPIC BeadChip检测血液来源DNA中鸟嘌呤核苷酸甲基化之前的胞嘧啶核苷酸。进行线性混合模型分析，将分叉处颈动脉IMT（bIMT）对鸟嘌呤核苷酸位点之前的胞嘧啶核苷酸的β值进行回归，并对协变量进行调整，随后进行差异甲基化区域（DMR）分析。进行单样本孟德尔随机化分析以研究DMR与bIMT之间的因果关联。25个DMR与bIMT相关（Sidak <0.05），最强的DMR（Sidak =2.45×10）与……的启动子重叠。DMR内鸟嘌呤核苷酸之前的所有11个胞嘧啶核苷酸均与bIMT呈正相关（=0.0007 - 0.00006）。DMR的甲基化与……变异相关，包括rs823154（β=0.26；=1.1×10）。如基因型 - 组织表达项目（GTEx）所报道，rs823154是多个组织（包括主动脉（=2.3×10）和血液（=4.0×10））中……的表达数量性状位点，这表明DMR的高甲基化导致该基因表达降低。孟德尔随机化分析支持DMR在bIMT中的因果作用（=0.049）。
我们的研究和先前的表达数量性状位点研究提供了一致的证据，即启动子高甲基化导致……表达降低与动脉粥样硬化增加相关。
