Despite intensive efforts, the primary abnormalities responsible for the pathogenesis of essential hypertension remain unknown. The knowledge that a large fraction of the population's variation in blood pressure is genetically-determined suggests the possibility of identifying the mutations which directly contribute to the pathogenesis of hypertension. Subdividing hypertension patients by using intermediate phenotypes, traits which are found to be present in some, but not all, hypertensive subjects, has the potential to substantially increase the power of such genetic approaches. Among such intermediate phenotypes, four to appear to show the most promise: 1) altered urinary kallikrein excretion; 2) elevated erythrocyte sodium-lithium countertransport; 3) non-modulation of adrenal and renal vascular responses to angiotensin II with changes in sodium intake; and 4) low plasma renin activity response to volume depletion. The physiology which underlies each of these intermediate phenotypes suggests a battery of underlying candidate genes, including genes of the renin- angiotensin system, the renal apical sodium/hydrogen antiporter, genes which regulate the activity of the antiporter, and members of the kallikrein gene family. In order to complete the study in a timely fashion, sibling pairs will be evaluated at each of three clinical centers -Boston, MA, Paris, France and Salt Lake City, UT. All patients will undergo a standard protocol to characterize the intermediate phenotype in each of the sibling pairs. We will then genotype sibling pairs and their parents with candidate gene markers in order to determine the alleles shared identically by descent by the sibling pairs at candidate gene loci. Using these data, we will test the hypothesis that mutations in one or more candidates genes contribute to the pathogenesis of essential hypertension by performing linkage analysis in hypertensive sibling pairs. The power of the analysis will be increased by stratifying sibling pairs for the presence or absence of intermediate phenotypes. By analogous methods, linkage between candidate loci and the intermediate phenotypes themselves will be investigated. It is anticipated that, at a minimum, we will be able to exclude a number of candidate locis as having a role in the pathogenesis of hypertension. Identification of linkage with any of the candidate genes to be studied would provide a major step toward unravelling the pathogenesis of this common disorder.
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