Hypergen: Genetics of Left Ventricular Hypertrophy

Hypergen：左心室肥大的遗传学

• 批准号: 7907610
• 负责人: Donna K Arnett
• 金额: $ 78.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-10 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907610
• 关键词: Address; Affect; African American; Arts; Blood Pressure; Candidate Disease Gene; Cardiovascular system; Complex; Congestive Heart Failure; Control Groups; DNA Resequencing; Data; Disease; Endothelin Receptor; Explosion; Family; Family member; Genes; Genetic; Genetic Markers; Genomics; Genotype; Haplotypes; Hypertension; Interleukin-15; Knowledge; Left Ventricular Hypertrophy; Light; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Maps; Measures; Methods; Modeling; Morbidity - disease rate; Myocardial Infarction; Nature; Neuropeptide Y Receptor; Parents; Pathway interactions; Peroxisome Proliferators; Phenotype; Play; Population; Predisposition; Preventive; Proteins; Quantitative Trait Loci; Race; Recruitment Activity; Research Personnel; Resources; Retinoid Receptor; Role; SNP genotyping; Sample Size; Services; Siblings; Signal Transduction; Source; Staging; Statistical Methods; Stroke; Technology; Testing; Therapeutic Intervention; Trees; Work; base; carboxypeptidase H; case control; clinically significant; cohort; cost; density; design; follow-up; genetic epidemiology; genetic linkage analysis; genetic pedigree; genetic variant; genome wide association study; genome-wide; improved; innovation; interest; mortality; normotensive; novel; offspring; proband; programs; receptor

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.

描述(申请人提供)：左心室肥厚(LVH)是一种常见的表型，发生在多达60%的高血压患者中，与显著的心血管死亡率有关。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名确诊为高血压的家族成员、652名随机选择的同一来源队列的受试者和247名确诊为正常血压的高血压家族成员的超声心动图测量数据。我们在受影响的高血压先证者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，对它们进行了重新测序以确认单倍型标记SNPs，并在无关的LVH病例和对照组中对SNPs进行了基因分型。我们发现左心室肥厚与所有候选基因(神经肽Y受体1、2和5、羧基肽酶E、白介素15、内皮素A受体、过氧化物酶体增殖物-激活物受体、维甲酸受体α和分泌的卷曲蛋白)之间存在显著的相关性。 2)。对于这次更新，我们将通过进行连锁分析来进一步完善我们的连锁结果，其中包括最近由哺乳动物基因分型服务进行了基因分型的高血压兄弟姐妹的后代(基因分型于2005年10月公布)。与这些较大的家系的连锁分析将提供比我们以前所能获得的更好的力量。为了进一步确定连锁区域的特征，我们将使用高密度(2kb)SNP基因分型，并对这些区域进行连锁不平衡图谱。为了成本效益，我们将使用提供全基因组覆盖的Affymetrix 500,000 SNP芯片，并在500个无关的病例-对照对中使用关联方法。我们将在FBPP(热那亚)的第二个种群中复制5000个SNP，并进一步描述我们最好的5个地区。最后，我们将为关联性研究实施新的统计方法。我们假设我们将确定在LVH中发挥临床重要作用的基因变异，这将为LVH预防或治疗干预提供新的途径。