Female gender & expression of risk genes in hypertension

描述：（改编自申请人摘要）高血压是心血管疾病的主要诱因，是美国女性死亡的主要原因。大多数关于高血压的研究都集中在男性身上。在50岁之前，女性高血压的发病率较低，而在50岁之前，女性高血压的发病率高于男性。由于50岁是美国女性绝经的平均年龄，这一观察结果表明，存在于绝经前状态的卵巢类固醇掩盖了高血压的遗传易感性，而在更年期失去这些类固醇，高血压的遗传易感性变得明显。这些工作者早期的研究表明，原发性高血压的一种特定的中间表型与血管紧张素原基因多态性有关，这种基因多态性导致肾素-血管紧张素-醛固酮系统（RAAS）的组织活性增加，这可能是高血压的原因。与年龄匹配的男性相比，这种表型在绝经前的高加索女性中并不常见，但在绝经后这种表型的频率增加，在男性和女性中变得相同。雌二醇对RAAS的许多基因有主要影响，因此是调节基因型表达的主要候选者，并负责绝经前和绝经后妇女表型频率的变化。这项建议的总目标是：1)验证绝经前高血压女性与绝经后高血压女性和男性的RAAS基因特异性多态性频率的差异；2)验证具有这些RAAS基因特异性多态性的绝经后高血压女性给予雌二醇会改变中间表型和降低血压的假设；3)根据三组的特定基因型检测组织RAAS的活性。

DESCRIPTION: (Adapted from the applicant's abstract) 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. Earlier studies by these workers have shown that a specific intermediate phenotype of essential hypertension is associated with polymorphism 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 Caucasian women compared to age-matched men but the frequency of this phenotype increased 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 polymorphism 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 estrasiol to postmenopausal hypertensive women with these specific polymorphism in RAAS genes will alter the intermediate phenotype and lower blood pressure, and 3) examine activity of the tissue RAAS according to specific genotypes in these three groups.