Psychosocial stress, epigenetics and health disparity in hypertension

摘要 原发性高血压(EH)仍然是一个严重的健康问题，存在显著的种族差异。与.相比 欧洲裔美国人(EA)、非裔美国人(AA)不仅EH的患病率更高，而且 特别容易受到EH的负面影响。越来越多的证据表明，累积暴露于 心理社会应激在EH的发生发展中起着重要作用。这些社会群体中的种族差异 EH的决定因素可能导致EH的种族差异。然而，人们对此知之甚少 将心理社会应激与EH早期病因联系起来的潜在分子机制。我们假设 在实验室环境下，暴露于慢性心理社会应激会对血压的急性应激反应产生不利影响 通过DNA甲基化和现实生活，影响EH早期临床前测量的进展 成年并在EH中达到顶峰。这项提议的基本目标是识别这些DNA 甲基化改变并评估它们在AAs和EAs中的作用是否不同。建立在我们的纵向基础上 佐治亚州心血管(CV)双胞胎研究，其中包括750对多种族双胞胎样本(375对双胞胎) 在18岁之前至少就诊一次，在18-26岁期间就诊一次，并在这次就诊时提供血液样本， 我们将进行一次额外的随访(年龄范围为30-42岁)。纵向双胞胎研究提供了一个 强大的设计，可同时控制DNA甲基化的遗传来源和可塑性。具体目标 是：(1)研究心理社会压力对DNA甲基化变化的联合和独特影响 成人期早。全基因组DNA甲基化和心理社会压力暴露将在18岁时获得- 26岁和30-42岁。CpG位点及其DNA甲基化水平与应激暴露和 随着暴露的变化而显示的变化将在我们的佐治亚州压力和心脏队列中得到验证。实时 还将对这些CpG位点±100kb内的基因进行PCR，以检查DNA甲基化 影响基因表达；(2)根据CpG位点的DNA甲基化水平确定它们的作用 高血压患者实验室和生活应激反应及临床前测量的社会心理因素 (3)测试目标1中确定的关系和 2取决于种族以及与心理社会压力相关的DNA甲基化变化是否会 潜在地解释了在EH的发展过程中AAs和EAs之间的健康差异。了解 潜在的生物和分子机制，通过这些机制，心理压力变成了“生物学的” 嵌入“将有可能提供新的治疗目标，并导致有效的预防和 降低AAS和社区EH风险的治疗策略。

ABSTRACT Essential hypertension (EH) remains a significant health problem with striking racial disparity. Compared with European Americans (EAs), African Americans (AAs) not only have a greater prevalence of EH but also are specifically prone to the negative effects of EH. Growing evidence indicated that cumulative exposure to psychosocial stress plays an important role in the development of EH. Racial differences in these social determinants of EH are likely to contribute to the racial differences in EH. However, little is known about the underlying molecular mechanisms linking psychosocial stress to early etiology of EH. We hypothesize that exposure to chronic psychosocial stress adversely affect BP response to acute stress both in laboratory setting and real life via DNA methylation, impacting the progression of preclinical measurement of EH in early adulthood and culminating in EH. The fundamental objective of this proposal is to identify these DNA methylation changes and evaluate whether their roles differ between AAs and EAs. Building on our longitudinal Georgia Cardiovascular (CV) Twin Study in which a multi-ethnic twin sample of 750 twins (375 twin pairs) having at least one visit before age 18 and one visit from age 18-26 with blood samples available at this visit, we will conduct one additional follow-up visit (age range 30-42 years). The longitudinal twin study provides a powerful design to control both the genetic sources and plastic nature of DNA methylation. The specific aims are: (1) To examine the joint and distinctive impacts of psychosocial stress on DNA methylation changes in early adulthood. Genome wide DNA methylation and psychosocial stress exposure will be obtained at age 18- 26 and age 30-42. The CpG sites with their DNA methylation levels associated with stress exposure and showing changes with changes in exposure will be validated in our Georgia Stress and Heart cohort. Real-time PCR will also be conducted on genes within ±100kb of these CpG sites to check whether DNA methylation affects gene expression; (2) To identify the CpG sites with their DNA methylation levels mediating the effect of psychosocial factors on BP response to laboratory and real-life stress and preclinical measurements of EH (pulse wave velocity and left ventricular mass); and (3) To test whether the relationship identified in aim 1 and 2 are dependent on ethnicity and whether psychosocial stress related DNA methylation changes can potentially explain the health disparity between AAs and EAs in the development of EH. Understanding the underlying biological and molecular mechanisms through which the psychological stress becomes “biologically embedded” will have the potential to provide new treatment target and lead to effective prevention and treatment strategies to reduce EH risks in both AAs and communities.