Essential hypertension is a multifactorial disorder with a Gaussian distribution and with a genetic component that appears to be polygenic and heterogeneous. The purpose of this project is to seek out genes or genetic markers which identify subjects more vulnerable to hypertension under the influence of environmental factors. The studies require clinical knowledge of the pathophysiology and therapy of hypertension, availability of a large racially diverse patient population and a General Clinical Research Center for recruitment, characterization and classification of subjects, in combination with knowledge of molecular biology for DNA preparation and expertise in molecular genetics and molecular epidemiology for genetic analysis. The five Specific Aims of this project are: 1) To classify hypertensives into relatively homogeneous subgroups according to intermediate phenotypes based on heritable biological traits, including anthropometric and neurohumoral data obtained by submitting selected subjects to a 3-day inpatient protocol, from which data may be extrapolated and applied to stratify larger subject populations in order to enhance efficacy of subsequent genetic analysis; 2) To genotype subjects for chromosomal loci using approximately 350 highly polymorphic microsatellite markers spaced every 5-10 cM along each chromosome. The strategy is to initially type markers in a select group of hypertensive kindreds that can independently demonstrate linkage; 3) To analyze the genetic marker data for linkage using both parametric (lod score) and nonparametric (affected-pedigree-member) methods. Suggestive findings will be pursued in the sib-pairs; 4) Case-control studies will be used to confirm positive linkage from aim 3 and to identify particular allele associations using methods of linkage disequilibrium and DNA pooling; 5) To screen and assess mutations in candidate genes linked to hypertension in patients and controls.
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