Wang Yi Zhe, Zhao Wei, Ammous Farah, Song Yanyi, Du Jiacong, Shang Lulu, Ratliff Scott M, Moore Kari, Kelly Kristen M, Needham Belinda L, Diez Roux Ana V, Liu Yongmei, Butler Kenneth R, Kardia Sharon L R, Mukherjee Bhramar, Zhou Xiang, Smith Jennifer A
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
Front Cardiovasc Med. 2022 May 19;9:848768. doi: 10.3389/fcvm.2022.848768. eCollection 2022.
Low socioeconomic status (SES) and living in a disadvantaged neighborhood are associated with poor cardiovascular health. Multiple lines of evidence have linked DNA methylation to both cardiovascular risk factors and social disadvantage indicators. However, limited research has investigated the role of DNA methylation in mediating the associations of individual- and neighborhood-level disadvantage with multiple cardiovascular risk factors in large, multi-ethnic, population-based cohorts. We examined whether disadvantage at the individual level (childhood and adult SES) and neighborhood level (summary neighborhood SES as assessed by Census data and social environment as assessed by perceptions of aesthetic quality, safety, and social cohesion) were associated with 11 cardiovascular risk factors including measures of obesity, diabetes, lipids, and hypertension in 1,154 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). For significant associations, we conducted epigenome-wide mediation analysis to identify methylation sites mediating the relationship between individual/neighborhood disadvantage and cardiovascular risk factors using the JT-Comp method that assesses sparse mediation effects under a composite null hypothesis. In models adjusting for age, sex, race/ethnicity, smoking, medication use, and genetic principal components of ancestry, epigenetic mediation was detected for the associations of adult SES with body mass index (BMI), insulin, and high-density lipoprotein cholesterol (HDL-C), as well as for the association between neighborhood socioeconomic disadvantage and HDL-C at FDR < 0.05. The 410 CpG mediators identified for the SES-BMI association were enriched for CpGs associated with gene expression (expression quantitative trait methylation loci, or eQTMs), and corresponding genes were enriched in antigen processing and presentation pathways. For cardiovascular risk factors other than BMI, most of the epigenetic mediators lost significance after controlling for BMI. However, 43 methylation sites showed evidence of mediating the neighborhood socioeconomic disadvantage and HDL-C association after BMI adjustment. The identified mediators were enriched for eQTMs, and corresponding genes were enriched in inflammatory and apoptotic pathways. Our findings support the hypothesis that DNA methylation acts as a mediator between individual- and neighborhood-level disadvantage and cardiovascular risk factors, and shed light on the potential underlying epigenetic pathways. Future studies are needed to fully elucidate the biological mechanisms that link social disadvantage to poor cardiovascular health.
社会经济地位低下（SES）以及生活在弱势社区与心血管健康状况不佳有关。多条证据表明，DNA甲基化与心血管危险因素及社会劣势指标均存在关联。然而，在大型、多民族、基于人群的队列研究中，针对DNA甲基化在介导个体层面和社区层面的劣势与多种心血管危险因素之间关联所起作用的研究有限。我们在动脉粥样硬化多民族研究（MESA）的1154名参与者中，考察了个体层面（儿童期和成人期SES）和社区层面（通过人口普查数据评估的社区SES汇总情况以及通过对审美质量、安全性和社会凝聚力的感知评估的社会环境）是否与11种心血管危险因素相关，这些危险因素包括肥胖、糖尿病、血脂和高血压的测量指标。对于显著关联，我们进行了全表观基因组中介分析，使用JT-Comp方法在复合零假设下评估稀疏中介效应，以识别介导个体/社区劣势与心血管危险因素之间关系的甲基化位点。在对年龄、性别、种族/民族、吸烟、药物使用和祖先遗传主成分进行调整的模型中，在错误发现率（FDR）<0.05时，检测到成人SES与体重指数（BMI）、胰岛素和高密度脂蛋白胆固醇（HDL-C）之间的关联存在表观遗传中介作用，以及社区社会经济劣势与HDL-C之间的关联也存在表观遗传中介作用。为SES-BMI关联确定的410个CpG中介位点富含与基因表达相关的CpG（表达数量性状甲基化位点，或eQTMs），且相应基因在抗原加工和呈递途径中富集。对于BMI以外的心血管危险因素，在控制BMI后，大多数表观遗传中介失去了显著性。然而，43个甲基化位点在BMI调整后显示出介导社区社会经济劣势与HDL-C关联的证据。所确定的中介位点富含eQTMs，且相应基因在炎症和凋亡途径中富集。我们的研究结果支持以下假设：DNA甲基化在个体层面和社区层面的劣势与心血管危险因素之间起中介作用，并揭示了潜在的表观遗传途径。未来需要开展研究以充分阐明将社会劣势与心血管健康不佳联系起来的生物学机制。
