GENETICS OF SALT SENSITIVITY IN AFRICAN AMERICANS

在非裔美国人中，动脉高血压的患病率、发病率和死亡率高得不成比例。原发性高血压是一种多基因异质性疾病。特别是，非裔美国人对盐的血压反应更大。人类盐敏感性高血压的细胞和分子机制仍然不明确，我们对潜在遗传机制的了解仍然不完整。我们最近观察到，与白人相比，健康的非肥胖非裔美国女性对盐挑战的血压反应增强。与白人相比，非洲裔美国人的细胞内钠含量也明显较高，钠泵活性（86 Rb摄取）也较低，这表明这些可能是盐敏感性高血压的重要表型标志物。事实上，细胞内钠的增加与一周低盐饮食和一周高盐饮食后收缩压的增加呈正相关，在非裔美国人中，而在白人中则没有。非裔美国人的钠泵呈反比关系。这项拟议的研究将对至少有两个来自非裔美国人的高血压余烬的兄弟姐妹进行遗传研究。强调基于高血压兄弟姐妹对的无模型遗传连锁分析方法，在人类或动物研究中与盐敏感性高血压相关的候选基因将根据这些中间表型和血压对盐挑战的反应进行评估。本研究的目的是：1)对160个兄弟姐妹中500名高血压兄弟姐妹的盐敏感性、细胞内钠、钠泵活性和蛋白质表达的中间表型进行表征，并对这些个体进行基因分型；在可能的情况下，这些受试者的父母也将进行基因分型，以便更好地通过血统关系确定身份。2)使用单变量和多变量方法评估与盐胁迫下血压变化幅度相关的各种候选基因座与中间表型的联系。该项目的总体目标是提高我们对非裔美国人盐敏感性高血压的遗传基础和表型特征的理解。为此，将仔细分析关注改进表型定义的发展，以及考虑基因-基因和基因-环境相互作用。

The prevalence, morbidity, and mortality of arterial hypertension are disproportionately high in the African-American population. Essential hypertension is a polygenic and heterogeneous disorder. In particular, African-Americans display an amplified blood pressure response to salt. The cellular and molecular mechanisms of salt-sensitive hypertension in humans remain poorly defined and our knowledge of potential genetic mechanisms remains incomplete. We recently observed an augmented blood pressure response to a salt challenge in healthy non-obese African- Americans females as compared to Whites. African-Americans also had significantly higher intracellular Na and depressed activity of the Na pump (86 Rb uptake)as compared to Whites suggesting these may be important phenotypic markers of salt-sensitive hypertension. In fact, an increase in intracellular Na was positively correlated with the increases in systolic blood pressure following one week of low salt vs one week of high salt diet in African-Americans but not in Whites. The inverse relationship was noted for the Na pump in African-Americans. The proposed study will carry out genetic studies of sibships with at least two hypertensive embers ascertained from the African-American population. Emphasizing model- free approaches to genetic linkage analysis based upon hypertensive sibling pairs, candidate genes that have been associated with salt-sensitive hypertension in either human or animal studies will be evaluated with respect to these intermediate phenotypes, and blood pressure responses to a salt challenge. The aims of this proposal are: l) To characterize the intermediate phenotypes of salt sensitivity, intracellular Na, sodium pump activity, and protein expression in a cohort of 500 hypertensive siblings in 160 sibships and to genotype these individuals; wherever possible, parents of these subjects will also be genotyped in order to better establish identity by descent relationships. 2) To assess linkage of the various candidate loci with intermediate phenotypes relating to the magnitude of blood pressure change with a salt challenge using univariate and multivariate approaches. The overall aim of this project is to improve our understanding of the genetic basis and phenotypic characterization of salt-sensitive hypertension in African Americans. To this end, careful analytic attention will be paid to the development of improved phenotype definition, as well as to the consideration of gene-gene and gene-environment interaction.