Genes of Hypertension in African Americans

描述(由申请人提供)：我们假设我们将能够通过专注于决定动脉压的生理途径来识别导致非裔美国人高血压的基因。在过去的6年里，我们广泛地描述了非裔美国人与心血管和肾功能相关的表型。基于最近完成的基因组扫描，我们已经确定了几个染色体区域，这些区域可能包含影响高血压和非裔美国人同胞对高血压相关表型的基因。对于几种表型，在相关研究中也发现了重叠的QTL，这些QTL存在于遗传隔离的法加群体中和/或在Dahl盐敏感x正常血压的Brown挪威鼠的F2杂交中的同源染色体区域。我们现在建议使用SNP基因组扫描方法，对500名高血压表型和500名正常血压的非裔美国人进行遗传关联研究。为了实现血压与高血压受试者的明确分离，正常血压受试者将从人群血压分布的较低三分之一中挑选出来。高血压(BMI)和年龄。表型的纳入是基于它们与高血压的病理生理学的相关性以及先前“遗传性”的证据。SNP分析的候选基因将被选择在两个QTL的染色体区域内，这两个QTL是我们之前已经证明与高血压相关的表型--1号染色体上的体重指数QTL和18号染色体上的微量白蛋白尿QTL。SNP分析将在每个QTL中的15%的基因中进行，并将根据它们与高血压的相关性来选择基因，包括记录的与大鼠或小鼠血压相关的QTL的序列保守性。该项目的最终目标是确定是否可以确定与血压相关的不同表型簇，从而将高血压个体划分为不同的亚组，以便于分析高血压的遗传决定因素和/或提供导致这些特征的基因的机制线索。

DESCRIPTION (provided by applicant): We hypothesize that we will be able to identify genes contributing to hypertension in African Americans by focusing on the physiological pathways that determine arterial pressure. Over the past 6 years, we have extensively characterized African Americans for phenotypes related to cardiovascular and renal function. Based on recently completed genome scans, we have identified several chromosomal regions likely to contain genes influencing hypertension-related phenotypes in hypertensive, African American sib pairs. For several phenotypes, overlapping QTLs have also been identified in related studies in a genetically isolated French Canadian population and/or in homologous chromosomal regions in the F2 cross of Dahl-salt sensitive x normotensive Brown Norway rats. We now propose to extensively phenotype 500 hypertensive and 500 normotensive African American subjects to conduct a genetic association study, using a SNP genomic scan approach. To achieve a clear separation of blood pressures from hypertensive subjects, normotensive subjects will be selected from the lower third of the population-based blood pressure distribution. Hypertensive (BMI), and age. Inclusion of phenotypes is based on their relevance to the pathophysiology of hypertension and prior evidence of "heritability." Candidate genes for SNP analysis will be selected within chromosomal regions of two QTLs that we have previously demonstrated to be linked to hypertension-related phenotypes--a QTL for body mass index on chromosome 1 and a QTL for microalbuminuria on chromosome 18. SNP analyses will be carried out in 15 percent of the genes within each of these QTLs, and genes will be selected on the basis of their relevance to hypertension, including documented sequence conservation for blood pressure related QTLs with rat or mouse. The final goal of the project is to determine if distinct clusters of blood pressure related phenotypes can be identified that will permit stratification of hypertensive individuals into distinct subgroups to facilitate the analysis of the genetic determinants of hypertension and/or provide mechanistic leads to genes contributing to these traits.