DNA 甲基化与年龄无关的心血管风险：基于表观基因组学的研究：REGICOR 研究（GIroní 注册研究中心）。
DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroní del COR).
机构信息
From the Cardiovascular Epidemiology and Genetics Research Group, REGICOR Study Group, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain (A.F.-S., S.S.-B., I.S., J.M., R.E.); Universitat Pompeu Fabra, Barcelona, Spain (A.F.-S., S.S.-B.); CIBER Cardiovascular Diseases, Barcelona, Spain (S.S.-B., J.M., R.E.); CIBER Epidemiology and Public Health (CIBERESP), Barcelona, Spain (I.S.); Centro Universitario de Investigación, Innovación y Diagnóstico Arterial (CUiiDARTE), Physiology Department, School of Medicine, Republic University, Montevideo, Uruguay (S.C.); and Medical School, University of Vic-Central University of Catalonia, Barcelona, Spain (R.E.).
出版信息
Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):645-652. doi: 10.1161/ATVBAHA.117.310340. Epub 2018 Jan 11.
OBJECTIVE
The objectives of this study were to decipher whether age-independent cardiovascular risk is associated with DNA methylation at 5'-cytosine-phosphate-guanine-3' (CpG) level and to determine whether these differential methylation signatures are associated with the incidence of cardiovascular events.
APPROACH AND RESULTS
We designed a 2-stage, cross-sectional, epigenome-wide association study. Age-independent cardiovascular risk calculation was based on vascular age and on the residuals of the relationship between age and cardiovascular risk. Blood DNA methylomes from 2 independent populations were profiled using the Infinium HumanMethylation450 BeadChip. The discovery stage of these studies was performed in the REGICOR cohort (REgistre GIroní del COR; n=645). Next, we validated the initial findings in the Framingham Offspring Study (n=2542). Eight CpGs located in 4 genes (, , , and ) and 3 intergenic regions showed differential methylation in association with age-independent cardiovascular risk (≤1.17×10). These CpGs explained 12.01% to 15.16% of the variability of age-independent cardiovascular risk in REGICOR and 7.51% to 8.53% in Framingham Offspring Study. Four of them were only related to smoking, 3 were related to smoking and body mass index, and 1 to diabetes mellitus, triglycerides levels, and body mass index (≤7.81×10). In addition, we developed methylation risk scores based on these CpGs and observed an association between these scores and cardiovascular disease incidence (hazard ratio=1.32; 95% confidence interval: 1.16-1.51).
CONCLUSIONS
Age-independent cardiovascular risk was related to different DNA methylation profiles, with 8 CpGs showing differential methylation patterns. Most of these CpGs were associated with smoking, and 3 of them were also related to body mass index. Risk scores based on these differential methylation patterns were associated with cardiovascular events and could be useful predictive indices.
目的
本研究旨在探讨独立于年龄的心血管风险是否与 5'-胞嘧啶-磷酸-鸟嘌呤-3'（CpG）水平的 DNA 甲基化有关，并确定这些差异甲基化特征是否与心血管事件的发生有关。
方法和结果
我们设计了一个 2 阶段、横断面、全基因组关联研究。独立于年龄的心血管风险计算基于血管年龄和年龄与心血管风险之间关系的残差。使用 Infinium HumanMethylation450 BeadChip 对来自两个独立人群的血液 DNA 甲基化组进行了分析。这些研究的发现阶段是在 REGICOR 队列（REGistre GIroní del COR；n=645）中进行的。接下来，我们在弗雷明汉后代研究（Framingham Offspring Study；n=2542）中验证了最初的发现。在 REGICOR 中，有 8 个位于 4 个基因（、、、和）和 3 个基因间区域的 CpG 与独立于年龄的心血管风险相关，其甲基化水平存在差异（≤1.17×10）。这些 CpG 解释了 REGICOR 中 12.01%至 15.16%的独立于年龄的心血管风险的变异性，在弗雷明汉后代研究中解释了 7.51%至 8.53%。其中 4 个与吸烟有关，3 个与吸烟和体重指数有关，1 个与糖尿病、甘油三酯水平和体重指数有关（≤7.81×10）。此外，我们基于这些 CpG 构建了甲基化风险评分，并观察到这些评分与心血管疾病发病率之间存在关联（危险比=1.32；95%置信区间：1.16-1.51）。
结论
独立于年龄的心血管风险与不同的 DNA 甲基化谱有关，其中 8 个 CpG 显示出差异甲基化模式。这些 CpG 中的大多数与吸烟有关，其中 3 个与体重指数也有关。基于这些差异甲基化模式的风险评分与心血管事件相关，可能是有用的预测指标。
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