GENETIC DETERMINANTS OF HIGH BLOOD PRESSURE

在本建议中，我们将采用几种协同策略， 确定高血压新遗传决定因素。我们的主要战略 将使用基因组标记（匿名标记和候选标记） 基因）以10 cM的平均密度跨越人类基因组进行检查 密歇根州特库姆塞的250名白色同胞与血压的遗传连锁 以及红细胞锂升高的中间表型特征， 钠逆转运，肾上腺素能亢进状态，减少 近端肾小管锂清除率（测量近端肾小管钠离子浓度） 处理）和肾素-血管紧张素系统的成分（血浆肾素和 血管紧张素转换酶活性和血清血管紧张素原 浓度）。阳性结果将通过进一步检测确认， 在伊利诺伊州梅伍德的250名非洲裔美国人同胞中进行了一项研究。 此外，我们将寻求开发新的高血压候选基因 通过分离与高血压表型相关的基因， 来自近交系正常血压和高血压品系的大鼠群体; 将在人类中寻找在大鼠中鉴定的基因的同源物。 在我们的兄弟姐妹中培养和提炼了重要的候选人， 模型，我们将测试协会在几个现存的黑人人口， 牙买加和尼日利亚以及特库姆塞和梅伍德的学科 从人群血压的极端值中选出 分布 为了进行这些调查，我们召集了- 适合鉴定的特征人口资源 受高血压影响的先证者和家庭（特库姆塞，MI和Maywood， IL），两个经验丰富的流行病学调查小组在 密歇根大学和芝加哥洛约拉大学，最先进的 由凯斯西方经验丰富的研究人员运行的基因分型设施 储备大学，一个卓越的统计遗传学家团队，一种动物 在确定遗传基因座方面具有生产力记录的资源 调节高血压大鼠的血压，以及一些相关的 适合病例对照研究的人口资源（尼日利亚、牙买加）。 我们相信，这些资源将使我们能够实现我们的目标。 主要目的是确定高血压的遗传决定因素。

In this proposal, we will employ several synergistic strategies to identify novel genetic determinants of hypertension. Our primary strategy will be to use genomic markers (both anonymous markers and candidate genes) spanning the human genome at an average density of 10 cM to examine 250 white sibships in Tecumseh, MI for genetic linkage with blood pressure and the intermediate phenotypic features of elevated erythrocyte lithium- sodium countertransport, the hyperkinetic hyperadrenergic state, decreased proximal tubular lithium clearance (a measure of proximal tubular sodium handling), and elements of the renin-angiotensin system (plasma renin and angiotensin-converting enzyme activity and serum angiotensinogen concentration). Positive findings will be confirmed by further testing for linkage in a population of 250 African-American sibships in Maywood, IL. In addition, we will seek to develop new candidate genes for hypertension by identifying genes linked to the hypertensive phenotype in segregating rat populations derived from inbred normotensive and hypertensive strains; homologues of genes identified in rats will be searched for in humans. Having developed and refined important candidates in our sibships and rat models, we will test associations in several extant black populations in Jamaica and Nigeria as well as in subjects in Tecumseh and Maywood selected from the extremes of the populational blood pressure distribution. To carry out these investigations, we have brought together well- characterized population resources suitable for the identification of probands and families affected by hypertension (Tecumseh, MI and Maywood, IL), two experienced teams of epidemiological investigators at the University of Michigan and Loyola University of Chicago, state-of-the-art genotyping facilities run by experienced investigators at Case Western Reserve University, a superb team of statistical geneticists, an animal resource with a proven record of productivity in identifying genetic loci regulating blood pressure in hypertensive rats, and several relevant population resources suitable for case-control studies (Nigeria, Jamaica). We are confident that these resources will permit us to accomplish our primary aim of identifying genetic determinants of hypertension.