Neurovascular Research Group, Department of Neurology of Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra , Barcelona, Spain.
Cardiovascular Epidemiology and Genetics Research Group, IMIM (Hospital del Mar Medical Research Institute) , Barcelona, Spain.
Epigenetics. 2020 Sep;15(9):988-997. doi: 10.1080/15592294.2020.1746507. Epub 2020 Apr 6.
DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1-2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism. To detect epigenetic variants associated with stroke occurrence and stroke subtypes. A two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischaemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N = 226 and N = 166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus , which includes known genetic variants associated with stroke. The pathways associated with these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.
DNA 甲基化是动态的，在整个生命过程中发生变化，其水平受生活方式和环境因素以及遗传变异的影响。迄今为止，在中风风险基因座中发现的主要遗传变异体仅能解释大约 1-2%的中风遗传率。这些单核苷酸多态性大多数位于由 DNA 酶 I 超敏位点标记的调控序列内，这表明涉及表观遗传机制。为了检测与中风发生和中风亚型相关的表观遗传变异体。设计了一个两阶段病例对照表观基因组全关联研究。发现样本有 401 个样本，包括在巴塞罗那的 Hospital del Mar 评估的 218 名缺血性中风 (IS) 患者和来自 REGICOR 队列的 183 名对照。在两个独立的样本 (N=226 和 N=166) 中，我们在 21 个基因座中复制了 22 个与 IS 中甲基化差异的 CpG 位点，包括已知与中风相关的基因座中的 2 个 CpG 位点。与这些基因座相关的途径是炎症和血管生成。荟萃分析确定了 384 个差异甲基化的 CpG 位点，包括已知的中风和血管风险遗传变异体的基因座，这些基因座富集了涉及脂质代谢、脂肪生成、昼夜节律和糖酵解途径的基因座。我们在 21 个基因座中确定了 22 个与 IS 相关的 CpG 位点。我们的分析表明，DNA 甲基化变化可能有助于协调导致 IS 的基因表达。
