Psychosocial stress, epigenetics and health disparity in hypertension

摘要 原发性高血压（EH）是一个重要的健康问题，具有显著的种族差异。较 欧洲裔美国人（EAs）、非洲裔美国人（AAs）不仅有更高的EH患病率， 特别容易受到EH的负面影响。越来越多的证据表明， 心理社会应激在EH的发生发展中起重要作用。这些社会中的种族差异 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 在实验室环境中，慢性心理社会应激对BP对急性应激的反应产生不利影响 和真实的生活中通过DNA甲基化，影响EH的临床前测量的进展， 成年期，并在EH中达到高潮。这项提案的基本目标是确定这些DNA 甲基化改变，并评估它们的作用是否在AA和EA之间不同。建立在我们的纵向 格鲁吉亚心血管（CV）双胞胎研究，其中包括750对双胞胎（375对双胞胎）的多种族双胞胎样本 在18岁之前至少有一次访视，在18-26岁之间至少有一次访视，并在该访视时提供血液样本， 我们将进行一次额外的随访访视（年龄范围30-42岁）。纵向双胞胎研究提供了一个 强大的设计来控制遗传来源和DNA甲基化的可塑性。具体目标 （1）研究心理社会应激对DNA甲基化改变的联合和独特影响， 成年早期全基因组DNA甲基化和心理社会压力暴露将在18岁时获得- 26岁30-42岁。CpG位点及其DNA甲基化水平与应激暴露相关， 在我们的格鲁吉亚压力和心脏队列中，将验证显示暴露量变化的变化。实时 还将对这些CpG位点± 100 kb内的基因进行PCR，以检查DNA甲基化是否 影响基因表达;（2）确定CpG位点及其DNA甲基化水平介导的影响， 影响血压对实验室和现实生活压力反应的心理社会因素以及EH的临床前测量 （脉搏波速度和左心室质量）;和（3）为了测试目标1和 2取决于种族，以及心理社会压力相关的DNA甲基化变化是否可以 可能解释AA和EA在EH发展中的健康差异。了解 潜在的生物和分子机制，通过这些机制，心理压力变得“生物学上”， 嵌入式”将有可能提供新的治疗靶点，并导致有效的预防， 治疗策略，以减少高血压风险在AA和社区。

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.