Epigenomic landscape of individual- and neighborhood-level social disadvantages and cardiovascular health disparity

摘要 由于心血管疾病（CVD）仍然是导致死亡的主要原因， 在美国的社区，迫切需要解决心血管疾病种族差异问题。个人层面 健康的社会决定因素（iSDH;例如，贫困和教育）和社区一级的SDH（nSDH） 与CVD风险因素以及亚临床和临床结局有关。接触SDH可能始于 年轻的年龄和积累的寿命。然而，大多数关于SDH和CVD的研究都集中在 老年人或老年人，而种族差异研究则侧重于自我报告的种族。纵向研究 从年轻时开始的SDH，也考虑遗传祖先与CVD种族差异的关系，是迫切需要的。 此外，目前衡量SDH的指数没有考虑到具体的健康结果，因此提供了 这些结果的信息有限。SDH和CVD之间的潜在生物学机制仍然存在 大部分未知。表观遗传标记与社会劣势和心血管疾病结局相关， 表观遗传过程代表SDH和CVD种族差异之间的潜在生物学介质。然而，在这方面， 大多数先前的研究是横截面的，并限于一个或两个时间点和/或使用在 疾病发展。这些局限性阻碍了我们研究表观基因组生物标志物的动态本质 以及它们在从SDH暴露到中年亚临床CVD的过程中的时间和/或介导作用， 然后在以后的生活中进入临床CVD。在这项拟议的研究中，我们使用社会表观遗传学来解决这些差距。 了解个体和社区水平SDH对DNA甲基化标记物影响的方法 以及SDH相关DNA甲基化标记物在CVD发展和差异中的介导/时间作用。 我们为开展这项研究做好了独特的准备，因为我们可以利用冠状动脉的现有资源 年轻人动脉风险发展（CARDIA）研究。CARDIA是一个以社区为基础的双胞胎队列， 来自美国四个大城市的18-30岁的个人，他们的社会劣势差异很大， 目前每5年随访一次，持续>35年。具体而言，我们建议（1）开发iSDH和nSDH指数， 和亚临床CVD特异性的轨迹;（2）鉴定SDH相关的DNAm生物标志物，并检查其 使用TOPMed现成的纵向表观基因组数据在CVD风险和差异中的作用;（3）检查遗传 使用TOPMed即用型，在SDH相关DNAm生物标志物中与CVD风险和差异相关的作用 WGS数据;（4）验证我们在其他TOPM队列中的发现，并部署用户友好的Web应用程序。 通过评估与SDH相关的CVD的多种可改变的风险因素，这项高度时间和成本的研究结果表明， 有效的研究对于针对高需求人群、针对个人定制干预措施以及 社区层面，并分配资源，以解决在美国和世界各地的社会劣势。

ABSTRACT As cardiovascular disease (CVD) remains the leading cause of death and disproportionately affects Black communities in the U.S., there is an urgent need to address cardiovascular racial disparities. Individual-level social determinants of health (iSDH; e.g., poverty and education) and neighborhood-level SDH (nSDH) have been linked to CVD risk factors, as well as subclinical and clinical outcomes. Exposure to SDH may start from young age and accumulate over the lifespan. However, most studies on SDH and CVD have focused on either older adults or the elderly, while racial disparity studies have focused on self-reported race. Longitudinal studies of SDH from young age that also consider genetic ancestry in relation to CVD racial disparity are urgently needed. Furthermore, current indices to measure SDH do not take specific health outcomes into account and thus provide limited information for these outcomes. The underlying biological mechanisms between SDH and CVD remain largely unknown. Epigenetic markers have been associated with social disadvantages and CVD outcomes, and epigenetic processes represent a potential biological mediator between SDH and CVD racial disparity. However, most prior studies are cross-sectional and limited to one or two time points and/or use samples collected after disease development. These limitations hinder us from studying the dynamic nature of epigenomic biomarkers and their temporal and/or mediating role on the process from SDH exposure to subclinical CVD at middle age, and then into clinical CVD later in life. In the proposed study, we address these gaps using a social epigenetic approach to understand the impact of the individual- and neighborhood-level SDH on DNA methylation markers and the mediating/temporal role of SDH-associated DNA methylation markers in CVD development and disparity. We are uniquely poised to conduct this study because we can leverage existing resources from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a community-based biracial cohort of individuals enrolled at ages 18–30 years from four large U.S. cities with large variations in social disadvantages, currently followed every 5 years for >35 years. Specifically, we propose (1) to develop iSDH and nSDH indices, and trajectories specific to subclinical CVD; (2) to identify SDH-associated DNAm biomarkers and examine their roles in CVD risk and disparity using TOPMed ready-to-use longitudinal epigenomic data; (3) to examine genetic roles in SDH-associated DNAm biomarkers in relation to CVD risk and disparity using TOPMed ready-to-use WGS data; and (4) to validate our findings in other TOPMed cohorts, and deploy a user-friendly web application. By evaluating multiple modifiable risk factors of CVD related to SDH, the findings from this highly time- and cost- effective study will be invaluable for targeting high-need populations, tailoring interventions at the individual and neighborhood levels, and distributing resources to tackle social disadvantages in the U.S. and worldwide.