GENETIC DETERMINANTS OF HIGH BLOOD PRESSURE

在这项提议中，我们将采用几种协同战略来 确定高血压的新遗传决定因素。我们的主要战略 将使用基因组标记(包括匿名标记和候选标记 基因)以平均10厘米的密度横跨人类基因组进行检查 密西西比州特库姆塞的250名白人兄弟姐妹与血压存在遗传关联 红细胞锂升高的中间表型特征-- 钠反转运，高动力高肾上腺素能状态，减少 近端肾小管锂离子清除量(近端肾小管钠离子的量度 处理)，以及肾素-血管紧张素系统的组成成分(血浆肾素和 血管紧张素转换酶活性与血清血管紧张素原 浓度)。阳性结果将通过进一步的检测得到确认 伊利诺伊州梅伍德250名非洲裔美国人兄弟会中的关联。 此外，我们将寻求开发新的高血压候选基因。 通过分离识别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老鼠种群； 在老鼠身上发现的基因的同源基因将在人类身上寻找。 在我们的兄弟姐妹和老鼠中培养和提炼了重要的候选人 模型，我们将在几个现存的黑人种群中测试关联性 牙买加和尼日利亚以及特库姆塞和梅伍德的科目 选自人群血压的极端 分发。 为了进行这些调查，我们汇集了大量的- 适合识别的具有特征的人口资源 受高血压影响的先证者和家庭(Tecumseh，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 凯斯韦斯特由经验丰富的调查人员运营的基因分型设施 储备大学，一支优秀的统计遗传学家团队，一只动物 在识别遗传基因座方面具有经过验证的生产力记录的资源 高血压大鼠的血压调节及其相关的几个问题 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完成我们的 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.