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.
- National Institute on Minority Health and Health Disparities
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