SELECTED CANDIDATE GENES IN HUMAN HYPERTENSION

原发性高血压（EH）的家族聚集性暗示遗传因素 在其病因学上。 我们建议通过以下方法来检验特定的遗传假设： 三种不同的策略应用于手头的家庭材料。 我们将 使用148个多重EH同胞，共296个EH同胞和15个 在20个样本中，每个家系至少有4名EH患者（4 - 10名） 在其他非重叠支助下已查明的亲属。 将检验两类假设： (1)肾素-血管紧张素系统可能直接参与病因学 高血压通过突变的肾素，血管紧张素原或血管紧张素-I 转化（ACE）酶基因。 (2)外周和中枢肾上腺素能系统已经被牵连在 EH的发病机制 我们将测试4种肾上腺素能受体的参与 亚型，α 1、α 2、β 1和β 2受体。 这些假设将通过连锁分析进行检验， 选择肾素的情况下，通过直接搜索DNA变体。 A. 连锁分析将包括三个组成部分： (1)基于串联的高度多态性遗传系统的开发 简单序列基序的重复，作为标记的信息内容 基因座决定了检测连锁的能力; (2)三个位点生化指标与基因型的联合分析 高血压病家系及同胞对RAS（REN、ANG和ACE） 科目; (3)高血压病与肾素-血管紧张素Ⅱ基因多态性连锁的同胞对分析 血管紧张素系统和肾上腺素能受体基因在高血压同胞中的表达 对. B。直接搜索肾素基因座的DNA变体将在 20例高血压患者， 通过化学物质的组合， 错配检测和直接DNA测序。

Familial aggregation of essential hypertension (EH) implies genetic factors in its etiology. We propose to test specific genetic hypotheses through three distinct strategies applied to familial material at hand. We will use 148 multiplex EH sibships with a total of 296 EH siblings and 15 pedigrees each with at least 4 EH subjects (4 to 10) among 20 sampled relatives already ascertained under other, non-overlapping support. Two classes of hypotheses will be tested: (1) the renin angiotensin system may be directly involved in the etiology of EH through mutations of the renin, angiotensinogen or angiotensin-I converting (ACE) enzyme genes. (2) Peripheral and central adrenergic systems have been implicated in the pathogenesis of EH. We will test the involvement of 4 adrenergic receptors subtypes, alpha1, alpha2, beta1 and beta2 receptors. These hypotheses will be tested either by linkage analysis or, in the select case of renin, by direct search for DNA variants. A. Linkage analysis will include three components: (1) The development of highly polymorphic genetic systems based on tandem repeats of simple sequence motifs, as the information content of marker loci critically determine the power to detect linkage; (2) Joint analysis of biochemical measurements and genotypes at three loci of the RAS (REN, ANG and ACE) in pedigrees and sib-pairs of hypertensive subjects; (3) Sib-pair analysis of linkage between EH and RFLPs of the renin- angiotensin system and adrenergic receptors genes in hypertensive sib- pairs. B. Direct search for DNA variants at the renin locus will be performed in 20 hypertensive subjects selected on the basis of immunoreactive renin in the extreme range of recorded values, through a combination of chemical mismatch detection and direct DNA sequencing.