Essential hypertension is a multifactorial and heterogeneous disorder with both genetic and environmental factors contributing to its pathogenesis. Evidence suggests that the inheritance of hypertension is complex with a least several major genes playing a role. Because of this complexity and since blood pressure is a continuous, quantitative variable, the detection of such genes is difficult if analysis is restricted to the ultimate phenotype (elevated blood pressure). One approach recently advocated is to identify """"""""intermediate phenotypes"""""""", that is biochemical or physiological component traits that represent early or intermediate steps which interact with other genetic and environmental factors and contribute to blood pressure differences. Investigation of the mode of inheritance of these intermediate phenotypes would allow identification of major gene effects which ultimately may suggest candidate genes causing or contributing to the pathogenesis of essential hypertension. We have investigated several candidate phenotypes differentiating black and white hypertensives over the past several years: plasma chromogranin A (CgA), urinary kallikrein activity, plasma dopamine-beta-hydroxylase activity (DBH), and autonomic challenge tests -- baroreflex sensitivity, cold pressor test and phentolamine blood pressure response. Some of these phenotypes involve the kidney, others involve the autonomic nervous system, whose efferent sympathetic limb is a crucial determinant of renal function. We now propose to study these phenotypes in black hypertensive pedigrees. The major objectives of this proposal are to test the following hypotheses in black pedigrees with multigenerational essential hypertension;: 1) That these biochemical and physiologic variations in black essential hypertensives represent intermediate phenotypes which are important in the pathogenesis of human essential hypertension. In particular, these phenotypes may be crucial in mediating hypertension in the black population. 2) That these abnormalities are inherited in a simple Mendelian (monogenic, single locus) fashion. 3) That candidate genes (loci) suggested by these phenotypes will have alleles that cosegregate with these intermediate phenotypes in black families with hereditary essential hypertension. These hypotheses will be tested by performing segregation analysis to search for major gene (Mendelian) effects and determine mode of inheritance of the phenotype, and ultimately, linkage analysis of the phenotype (and it's candidate gene's alleles) to blood pressure in black families with multigenerational hypertension.
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