Hypergen: Genetics of Left Ventricular Hypertrophy

描述（由申请人提供）：左心室肥厚（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2951名确定为高血压的家庭成员、652名随机选择的来自同一来源队列的受试者和247名确定为正常LVH的家庭成员的超声心动图测量结果。我们在受影响的高血压先证和兄弟姐妹中确定了几个LVH连锁区域，对这些区域进行了精细定位，确定了位置候选基因，对它们进行了重测序，以确认单倍型标记snp，并在不相关的LVH病例和对照中对snp进行了基因分型。我们发现LVH与除一种外的所有候选位点（神经肽Y受体1、2和5、羧基肽酶E、白介素-15、内皮素受体A、过氧化物酶体增殖激活剂受体、类视黄醇受体α和分泌的卷曲蛋白）之间存在显著关联

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.