GENETIC DETERMINANTS OF HYPERTENSION

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In this application we propose to map the major genetic loci underlying hypertension in 1700 sibling pairs of Asian-Pacific Chinese and Japanese origin. We will focus our investigation on this population in order to reduce heterogeneity of the genetic background. We will first establish a genetic network in the San Francisco Bay Area, Hawaii, and Taiwan, recruiting 1700 affected hypertensive sibpairs plus several mutigenerational hypertensive pedigrees. We will then map and identify the genes for hypertension in this ethnic group using linkage analyses. A new genetic map of the human genome with 2041 ordered polymorphic markers with an average interval of less than 3 cM has been reported. Such a dense map of polymorphic markers makes it plausible to propose linkage analyses of complex traits. We propose to perform total genomic search on 1700 affected sibpairs and family members. In addition, we will also employ the candidate gene approach to examine the contribution of specific genes. To address the possibility of heterogeneity of the hypertensive trait, we will study a number of intermediate phenotypes that may help us identify a more homogeneous subgroups of hypertension. For example, Asians and Pacific Islanders have an increased risk for hypertension, dyslipidemia, and glucose intolerance (Syndrome X) that are associated with hyperinsulinemia. We will study hypertension according to insulin sensitivity vs. resistance as well as other intermediate phenotypes related to hypertension pathophysiology (e.g. renin, Ang II, endothelin). It is our hypothesis that by focusing on possible hypertensive subsets with well defined phenotypes, we will enhance the possibility of gene identification for hypertension in these patients. The third approach is to examine the hypothesis that there exists a dominant locus determining hypertension in a subset of affected individuals using the analysis of multigenerational pedigrees with 10-13 meiosis separating affected members. If such a subset exists, this approach would reduce the likelihood of heterogeneity and increase the probability of revealing genetic linkage. Once major gene loci are identified, it will be important to determine the prevalence of these loci in the overall population and the risk associated with their loci for the development of hypertension. Therefore, the genetic epidemiology of the loci will be studied using epidemiological methodologies such as association studies and case control analysis on well characterized populations (in Hawaii and Taiwan) that have been studied prospectively for many years.