GENETIC DETERMINANTS OF HYPERTENSION

在这项应用中，我们建议绘制潜在的主要遗传基因座 1700对亚太地区中国人和日本人兄弟姐妹高血压的研究 起源。我们将把调查的重点放在这一人群上，以便 减少遗传背景的异质性。我们将首先建立一个 旧金山湾区、夏威夷和台湾的基因网络， 招募1700对受高血压影响的同胞和几个人 多代高血压家系。然后，我们将绘制并识别 使用连锁分析研究该民族人群中高血压的基因。一种新的 具有2041个有序多态标记的人类基因组遗传图谱 据报道，平均间隔不到3厘米。如此密集的地图 多态标记的出现使提出连锁分析成为可能 复杂的特征。我们建议在1700进行全基因组搜索 受影响的兄弟姐妹和家庭成员。此外，我们还将聘请 候选基因法考察特定基因的贡献。至 考虑到高血压特征的异质性的可能性，我们 将研究一些中间表型，这些表型可能有助于我们识别 高血压的一个更同质性的亚组。例如，亚洲人和 太平洋岛民患高血压、血脂异常的风险增加， 和葡萄糖不耐受(X综合征)相关的 高胰岛素血症。我们将根据胰岛素来研究高血压 敏感性与抗性以及其他中间表型 与高血压的病理生理学相关(如肾素、血管紧张素II、内皮素)。 我们的假设是，通过关注可能的高血压亚群 有了明确的表型，我们将提高基因 对这些患者进行高血压的鉴定。第三种方法是 来检验这样的假设：存在一个决定的显性轨迹 对部分受影响个体的高血压情况进行分析 减数分裂10-13分离的多世代家系 会员。如果存在这样的子集，则此方法将减少 异质性的可能性和增加揭示的概率 基因连锁。一旦确定了主要的基因位点，这将是重要的 以确定这些基因座在总体人群中的患病率以及 与他们的基因座发生高血压相关的风险。 因此，这些基因座的遗传流行病学将使用 流行病学方法，如关联研究和病例控制 对特征良好的人群(夏威夷和台湾)的分析 已经前瞻性地研究了很多年。

In this application we propose to map the major genetic loci underlying hypertension in 1700 sibling pairs of Asian-Pacific Chinese and Japanese origin. We will focus our investigation on this population in order to reduce heterogeneity of the genetic background. We will first establish a genetic network in the San Francisco Bay Area, Hawaii, and Taiwan, recruiting 1700 affected hypertensive sibpairs plus several mutigenerational hypertensive pedigrees. We will then map and identify the genes for hypertension in this ethnic group using linkage analyses. A new genetic map of the human genome with 2041 ordered polymorphic markers with an average interval of less than 3 cM has been reported. Such a dense map of polymorphic markers makes it plausible to propose linkage analyses of complex traits. We propose to perform total genomic search on 1700 affected sibpairs and family members. In addition, we will also employ the candidate gene approach to examine the contribution of specific genes. To address the possibility of heterogeneity of the hypertensive trait, we will study a number of intermediate phenotypes that may help us identify a more homogeneous subgroups of hypertension. For example, Asians and Pacific Islanders have an increased risk for hypertension, dyslipidemia, and glucose intolerance (Syndrome X) that are associated with hyperinsulinemia. We will study hypertension according to insulin sensitivity vs. resistance as well as other intermediate phenotypes related to hypertension pathophysiology (e.g. renin, Ang II, endothelin). It is our hypothesis that by focusing on possible hypertensive subsets with well defined phenotypes, we will enhance the possibility of gene identification for hypertension in these patients. The third approach is to examine the hypothesis that there exists a dominant locus determining hypertension in a subset of affected individuals using the analysis of multigenerational pedigrees with 10-13 meiosis separating affected members. If such a subset exists, this approach would reduce the likelihood of heterogeneity and increase the probability of revealing genetic linkage. Once major gene loci are identified, it will be important to determine the prevalence of these loci in the overall population and the risk associated with their loci for the development of hypertension. Therefore, the genetic epidemiology of the loci will be studied using epidemiological methodologies such as association studies and case control analysis on well characterized populations (in Hawaii and Taiwan) that have been studied prospectively for many years.