Hypergen: Genetics of Left Ventricular Hypertrophy

描述（由申请人提供）：左心室肥大（LVH）是一种常见的表型，发生在高达60%的高血压患者中，与显著的心血管死亡率相关。作为家庭血压计划（FBPP）高血压遗传流行病学网络（HyperGEN）的辅助，我们收集了2，951名高血压家庭成员的超声心动图测量结果，652名来自同一来源队列的随机选择的受试者，以及247名血压正常的LVH家庭成员。我们在高血压先证者和兄弟姐妹中发现了几个LVH连锁区域，精细定位这些区域，确定位置候选基因，重新测序以确认单倍型标记SNP，并在无关LVH病例和对照中对SNP进行基因分型。我们发现LVH与所有的候选位置（神经肽Y受体1、2和5、羧肽酶E、白细胞介素-15、内皮素受体A、过氧化物酶体增殖物激活物受体、维甲酸受体α和分泌型卷曲蛋白）都有显著的相关性 2）。对于这次更新，我们将通过进行连锁分析进一步完善我们的连锁结果，包括最近由哺乳动物基因分型服务（基因型于2005年10月发布）进行基因分型的高血压兄弟姐妹的后代。与这些较大的家系连锁分析将提供更好的权力比我们以前。为了进一步表征连锁区域，我们将使用高密度（2 kb）SNP基因分型并对这些区域进行连锁不平衡作图。出于成本效益考虑，我们将使用Affysse500，000 SNP芯片，该芯片提供全基因组覆盖，并在500个不相关的病例-对照对中使用关联方法。我们将在FBPP（GENOA）的第二个群体中复制5，000个SNP，并进一步表征我们的5个最佳区域。最后，我们将实施新的统计方法进行关联研究。我们假设，我们将确定在LVH中发挥临床重要作用的遗传变异，这将为LVH的预防或治疗干预提供新的途径。

DESCRIPTION (provided by applicant): Left ventricular hypertrophy (LVH) is a common phenotype, occurring in up to 60% of hypertensives that is associated with significant cardiovascular mortality. Ancillary to the Hypertension Genetic Epidemiology Network (HyperGEN) of the Family Blood Pressure Program (FBPP), we collected echocardiographic measures on 2,951 family members ascertained on hypertension, 652 randomly-selected subjects from the same source cohorts, and 247 family members ascertained for normotensive LVH. We identified several LVH linkage regions in affected hypertensive probands and siblings, fine mapped the regions, identified positional candidate genes, resequenced them to confirm haplotype tagging SNPs, and genotyped SNPs in unrelated LVH cases and controls. We found significant associations between LVH and all but one of the positional candidates (neuropeptide Y receptors 1, 2, and 5, carboxypeptidase E, interleukin-15, endothelin receptor A, peroxisome proliferator-activator receptor, retinoid receptor alpha, and secreted frizzled protein 2). For this renewal, we will further refine our linkage results by conducting linkage analyses that include the offspring of the hypertensive siblings who were recently genotyped by the Mammalian Genotyping Service (genotypes were released in October, 2005). Linkage analysis with these larger pedigrees will provide better power than was available to us previously. To further characterize linkage regions, we will use high-density (2 kb) SNP genotyping and conduct linkage disequilibrium mapping of these regions. For cost-efficiency, we will use the Affymetrix 500,000 SNP chip that provides genome-wide coverage, and use association methods in 500 unrelated cases-control pairs. We will replicate 5,000 SNPs in a second population from the FBPP (GENOA), and further characterize our 5 best regions. Finally, we will implement novel statistical methods for association studies. We hypothesize that we will identify genetic variants that play clinically significant roles in LVH, and that will suggest novel pathways for LVH preventive or therapeutic interventions.