Essential hypertension is a common disorder that contributes to morbidity, mortality, and cost of health care in the population-at-large, particularly among African-Americans. Although thiazide diuretics are commonly prescribed for treatment of hypertension, blood pressure decreases in response to diuretic therapy individuals within each ethnic group. The overall objective of the proposed research is to determine whether direct measures of gene variation will improve our ability to predict interindividual differences in blood pressure response to diuretic therapy in African-Americans and in non-Hispanic Whites. Blood pressure response to diuretic therapy is in part dependent on the counterregulatory response of the renin-angiotensin-aldosterone (RAA) system to sodium and volume loss. Individuals who respond to diuretic therapy with a decrease in blood pressure are characterized by a low plasma renin activity that increases minimally in response to sodium and volume loss. Although responses of the RAA system and blood pressure to sodium and volume loss are known to be influenced by genetic variation, the specific genes responsible have not been identified. The proposed research will determine whether measured variation in genes coding for components of the RAA system predicts interindividual differences in blood pressure response to diuretic therapy in 300 hypertensive African-Americans and in 300 hypertensive non-hispanic Whites (600 individuals, total). We will conduct a standardized clinical study protocol in which hypertensive individuals, ages 30-59.9 years, are treated with the diuretic hydrochlorothiazide, 25 mg/day, for four weeks. We will measure interindividual variation in five RAA system genes: angiotensinogen, renin, angiotensin-I converting enzyme, angiotensin-II receptor, and aldosterone synthase; activity of the RAA system as reflected in levels of plasma angiotensinogen, renin activity, aldosterone, serum angiotensin-I converting enzyme, and urinary aldosterone excretion; concomitant variables; and blood pressure levels. The following specific aims will be accomplished in each ethnic group: to determine whether variation in genes of the RAA system predicts interindividual differences in blood pressure to diuretic therapy; determine whether variation in genes of the RAA system predicts interindividual differences in baseline measures of the endocrine RAA system or response of these measures to diuretic therapy.
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