GENETIC EXPRESSION OF RISK GENES IN HYPERTENSION

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DESCRIPTION (Verbatim from the application): Hypertension is a major contributor to cardiovascular disease, the leading cause of death in US women. Most studies of hypertension have focused on men. Women have a lower incidence of hypertension until age 50 at which time, the incidence of hypertension in women becomes greater than that in men. Since age 50 is the average age of menopause in US women, this observation suggests that ovarian steroids, present in the premenopausal state, mask genetic predisposition to hypertension and that with loss of these steroids at menopause, genetic predisposition to hypertension becomes manifest. We have shown that a specific intermediate phenotype of essential hypertension is associated with polymorphisms of the angiotensinogen gene which result in greater tissue activity of the renin-angiotensin-aldosterone system (RAAS) as a possible cause of hypertension. This phenotype is uncommon in premenopausal women compared to age-matched men but the frequency of this phenotype increases at menopause becoming equal in men and women. Estradiol has major effects on many of the genes of the RAAS and therefore is a prime candidate for modulating the expression of genotype and being responsible for the change in phenotype frequency in pre versus postmenopausal women. The overall objectives of this proposal are to: 1) demonstrate a difference in frequency of specific polymorphisms of genes of the RAAS in premenopausal hypertensive women as compare to hypertensive postmenopausal women and men, 2) test the hypothesis that the administration of estradiol to postmenopausal hypertensive women with these specific polymorphisms in RAAS genes will alter the intermediate phenotype and lower blood pressure, 3) examine activity of the tissue RAAS according to specific genotypes in these three groups.