This revised application requests support to investigate the genetic determinants of hypertension (HTN) in three populations of the African diaspora, with a major focus on clarifying the role of genes that code for the renin-angiotensin system (RAS). The primary goals of this study are: i) Determine the extent to which genetic variability of the RAS genes influences the distribution of blood pressure (and of RAS intermediate phenotypes) within each population, and contrast the results across populations; 2) Use family studies, within each population, to determine the degree-of familial aggregation of blood pressure, and of the RAS intermediate phenotypes; 3) Use segregation analysis to determine the contribution of """"""""major genes"""""""" to the familial aggregation of BP and of HTN, and determine whether RAS genes cosegregate with HTN, or with RAS intermediate phenotypes; 4) Evaluate whether the different prevalence of HTN in each community reflects differences in their genetic background. The study sites include Ibadan, Nigeria, Kingston, Jamaica, and Maywood, IL. At each site, genetic and epidemiological data will be collected from 800 individuals, sampled as follows: 500 individuals comprising 100 five- member structured family sets (proband, spouse, two sibs, one offspring, or half-sib), equally ascertained from the highest and lowest quartiles of the blood pressure distribution, as defined by an ongoing community-wide survey; 300 unrelated singletons, also sampled equally from the highest and lowest BP quartiles. The following measurements will be obtained from all participants. Epidemiological variables: BP, height, weight, waist/hip ratio, skinfolds, urine Na/K and sociodemographic variables; Intermediate phenotypes: Plasma levels of angiotensinogen, renin and angiotensin- converting enzyme (ACE); Genotypes: A set of DNA polymorphisms at the 4 main RAS loci (angiotensinogen, renin, ACE and the angiotensin II-type l receptor). This community-based study in 3 geographically distinct populations of West African heritage with contrasting levels of HTN risk will be the first comprehensive examination of the genetics of HTN in African Americans. We focus on the renin-angiotensin system because it is the only physiological arm of blood pressure control for which candidate genes have been securely linked to the risk of HTN. Polymorphisms at the angiotensinogen locus vary considerably between blacks and whites, while greater similarities are apparent for ACE. Preliminary data are available demonstrating that ACE genotype determines ACE levels in our populations, as observed among whites. In addition, an effect of ACE genotype on obesity has been observed among men. The documented black:white differences in the RAS system emphasize the importance of determining whether RAS genes contribute to the excessively high risk of HTN experienced by African Americans. This study will generate unique information about the variability of the RAS loci in populations of West African heritage, and the contribution of this variability to HTN risk. The data from this study, including the DNA specimens, will also represent a valuable resource for future work on the genetics of HTN in this important ethnic group.
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