Davis Armstrong Nicole M, Chen Wei-Min, Brewer Michael S, Williams Stephen R, Sale Michèle M, Worrall Bradford B, Keene Keith L
Department of Biology, East Carolina University, Greenville, NC, United States.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.
Front Genet. 2018 Sep 6;9:358. doi: 10.3389/fgene.2018.00358. eCollection 2018.
DNA methylation, a well-characterized epigenetic modification that is influenced by both environment and genetic variation, has previously been implicated in a number of complex diseases, including cardiovascular disease and stroke. The goal of this study was to evaluate epigenome-wide associations with recurrent stroke and the folate one-carbon metabolism-related trait, plasma homocysteine (hcy). Differential methylation analyses were performed on 473,864 autosomal CpG loci, using Illumina HumanMethylation 450K array data in 180 ischemic stroke cases from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial. Linear regression was used to assess associations between number of strokes prior to VISP enrollment and measures of hcy with degree of methylation (β-values), while logistic regression was used to evaluate recurrent stroke status and incident recurrent stroke associations. All regression analyses were stratified by race. Two differentially methylated CpG sites exceeded epigenome-wide significance ( ≤ 1.055 × 10) for prior number of strokes (PNS) in European Americans. The top locus, cg22812874, was located in the ankyrin repeat and SOCS box containing 10 gene (; = 3.4 × 10; β = -0.0308; 95% CI = -0.040, -0.002). Methylation locus cg00340919, located in an intron of the tetratricopeptide repeat domain 37 gene, was also statistically significant (; = 8.74 × 10; β = -0.0517; 95% CI = -0.069, -0.034). An additional 138 CpG sites met our threshold for suggestive significance ( ≤ 5 × 10). We evaluated DNA methylation associated with recurrent stroke and hcy phenotypes across the epigenome. Hypermethylation at two CpG sites located in and was associated with fewer strokes prior to VISP enrollment. Our findings present a foundation for additional epigenome-wide studies, as well as mechanistic studies into epigenetic marks that influence recurrent stroke risk.
DNA甲基化是一种特征明确的表观遗传修饰，受环境和基因变异的影响，此前已被认为与包括心血管疾病和中风在内的多种复杂疾病有关。本研究的目的是评估全表观基因组与复发性中风以及与叶酸一碳代谢相关的性状——血浆同型半胱氨酸（hcy）之间的关联。利用来自维生素预防中风干预（VISP）临床试验的180例缺血性中风病例的Illumina HumanMethylation 450K阵列数据，对473,864个常染色体CpG位点进行了差异甲基化分析。采用线性回归评估VISP入组前中风次数与hcy测量值与甲基化程度（β值）之间的关联，同时采用逻辑回归评估复发性中风状态和复发性中风事件的关联。所有回归分析均按种族分层。在欧洲裔美国人中，有两个差异甲基化的CpG位点在全表观基因组水平上具有显著性（≤1.055×10），与既往中风次数（PNS）相关。排名最靠前的位点cg22812874位于锚蛋白重复序列和含SOCS盒蛋白10基因中（P = 3.4×10；β = -0.0308；95%置信区间 = -0.040，-0.002）。位于四肽重复结构域37基因内含子中的甲基化位点cg00340919也具有统计学显著性（P = 8.74×10；β = -0.0517；95%置信区间 = -0.069，-0.034）。另外138个CpG位点达到了我们提示性显著性的阈值（≤5×10）。我们评估了全表观基因组范围内与复发性中风和hcy表型相关的DNA甲基化。位于和中的两个CpG位点的高甲基化与VISP入组前较少的中风次数相关。我们的研究结果为进一步的全表观基因组研究以及对影响复发性中风风险的表观遗传标记的机制研究奠定了基础。
