Racial Genomic Differences and Heart Failure Outcomes

种族基因组差异和心力衰竭结果

基本信息

批准号：
8037070
负责人：
DENNIS M. MCNAMARA
金额：
$ 16.1万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037070
关键词：
Activities of Daily Living Address Admixture Adrenergic Agents Adrenergic beta-Antagonists Adverse effects Affect African African American Aldosterone Synthase Alleles American Angiotensin II Angiotensin-Converting Enzyme Inhibitors Aspartic Acid Caliber Cardiovascular Diseases Cardiovascular system Chronic Clinical Clinical Research Clinical Trials Codon Nucleotides Data Disease Disease-Free Survival Dose Echocardiography Enalapril Enrollment Epidemic European Exons Frequencies Functional disorder GNB3 gene Gene Frequency Genes Genetic Genetic Heterogeneity Genetic Polymorphism Genetic Variation Genomics Genotype Glutamic Acid Haplotypes Heart failure Heterogeneity Hospitalization Hydralazine Hypertension Isosorbide Dinitrate Left Ventricular Ejection Fraction Left Ventricular Function Left Ventricular Hypertrophy Link Linkage Disequilibrium Low Prevalence Maps Mediator of activation protein Medical Mentors Methodology NOS3 gene Nitrates Nucleotides Outcome Outcomes Research Pathogenesis Pharmacogenetics Pharmacotherapy Phenotype Plasma Population Population Study Prevalence Principal Investigator Race Renin Research Personnel Risk Serum Universities Variant Vasodilator Agents adrenergic base black subgroup cohort gene interaction genetic variant human NOS3 protein improved programs promoter racial difference response

Activities of Daily Living Address Admixture Adrenergic Agents Adrenergic beta-Antagonists Adverse effects Affect African African American Aldosterone Synthase Alleles American Angiotensin II Angiotensin-Converting Enzyme Inhibitors Aspartic Acid Caliber Cardiovascular Diseases Cardiovascular system Chronic Clinical Clinical Research Clinical Trials Codon Nucleotides Data Disease Disease-Free Survival Dose Echocardiography Enalapril Enrollment Epidemic European Exons Frequencies Functional disorder GNB3 gene Gene Frequency Genes Genetic Genetic Heterogeneity Genetic Polymorphism Genetic Variation Genomics Genotype Glutamic Acid Haplotypes Heart failure Heterogeneity Hospitalization Hydralazine Hypertension Isosorbide Dinitrate Left Ventricular Ejection Fraction Left Ventricular Function Left Ventricular Hypertrophy Link Linkage Disequilibrium Low Prevalence Maps Mediator of activation protein Medical Mentors Methodology NOS3 gene Nitrates Nucleotides Outcome Outcomes Research Pathogenesis Pharmacogenetics Pharmacotherapy Phenotype Plasma Population Population Study Prevalence Principal Investigator Race Renin Research Personnel Risk Serum Universities Variant Vasodilator Agents adrenergic base black subgroup cohort gene interaction genetic variant human NOS3 protein improved programs promoter racial difference response

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项目摘要

DESCRIPTION (provided by applicant): In subjects with heart failure, genetic variation will affect clinical outcomes and the response to therapy. Heart failure is a polygenic disorder, and the impact of specific genetic polymorphisms will be influenced by genetic background. For several genes critical to heart failure pathogenesis, the prevalence of adverse alleles differs significantly between white and black cohorts. The current proposal will enroll one thousand subjects with heart failure due to systolic dysfunction including 500 white subjects and 500 black subjects, and will examine the impact of racial differences in genetic background on left ventricular function and clinical outcomes. Specific Aim 1 will evaluate the impact of genetic background on left ventricular ejection fraction (LVEF) and LV diastolic diameter in 500 black subjects with chronic heart failure and a matched cohort of 500 white subjects. The proposal will focus on adverse alleles of key heart failure mediators including the ACE deletion, aldosterone synthase promoter -344C, NOS3 Asp298, and betal Arg389 variants. Specific Aim 2 will investigate the impact of the adverse alleles from aim 1 on survival in the overall cohort and separately in the black and white subsets. Specific aim 3 will explore gene-gene interactions to examine whether the impact of the ACE D allele is modified by coinheritance of the GNB3 T haplotype. This polymorphism is linked to increased alpha adrenergic activation and low plasma renin and is far more prevalent in black cohorts. Specific Aim 3 will explore in the black heart failure cohort the use of Mapping by Admixture Linkage Disequilibrium (MALD), which utilizes comparisons of genomic DMA of African and European orgin, to determine the potential contributions of genomics to apparent racial differences in remodeling and heart failure outcomes. This proposal will address an important clinical question and will provide an ideal program for mentoring young investigators in the methodologies involved in genetics outcomes research.

描述（由申请人提供）：在患有心力衰竭的受试者中，遗传变异将影响临床结果和对治疗的反应。心力衰竭是一种多基因疾病，特定遗传多态性的影响将受遗传背景的影响。对于对心力衰竭发病机理至关重要的几种基因，白色和黑色同胞之间的不良等位基因的流行率显着不同。当前的提案将由于收缩功能障碍（包括500名白人受试者和500名黑人受试者）而招募一千名患有心力衰竭的受试者，并将检查种族差异对遗传背景对左心室功能和临床结果的影响。具体目标1将评估遗传背景对500名黑色受试者的左心室射血分数（LVEF）和LV舒张直径的影响，具有慢性心力衰竭和匹配的500名白色受试者的队列。该提案将集中于关键心力衰竭介质的不良等位基因，包括ACE缺失，醛固酮合酶启动子-344C，NOS3 ASP298和BETAL ARG389变体。特定的目标2将研究AIM 1的不良等位基因对整个队列中生存的影响，并在黑白子集中分别研究。特定的目标3将探索基因 - 基因的相互作用，以检查ACE D等位基因的影响是否通过GNB3 T单倍型的共同作用来改变。这种多态性与α肾上腺素能激活增加和血浆肾素低有关，在黑色队列中更为普遍。特定的目标3将在黑色心力衰竭队列中探索使用混合链接不平衡（MALD）对映射的使用，该构图利用了非洲和欧洲Orgin的基因组DMA的比较来确定基因组学对重塑和心脏失败的明显种族差异的潜在贡献。该建议将解决一个重要的临床问题，并将为指导年轻研究者提供遗传学结果研究的方法论提供理想的计划。