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

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，特定基因多态性的影响会受到遗传背景的影响。对于心力衰竭发病机制至关重要的几种基因，不良等位基因的患病率在白人和黑人群体之间存在显着差异。目前的提案将招募 1000 名因收缩功能障碍而患有心力衰竭的受试者，其中包括 500 名白人受试者和 500 名黑人受试者，并将研究遗传背景的种族差异对左心室功能和临床结果的影响。具体目标 1 将评估 500 名患有慢性心力衰竭的黑人受试者和 500 名白人受试者的匹配队列中遗传背景对左心室射血分数 (LVEF) 和左心室舒张直径的影响。该提案将重点关注关键心力衰竭介质的不利等位基因，包括 ACE 缺失、醛固酮合酶启动子 -344C、NOS3 Asp298 和 beta Arg389 变体。具体目标 2 将研究目标 1 中的不利等位基因对整个队列以及黑人和白人亚群中单独生存的影响。具体目标 3 将探索基因间相互作用，以检查 ACE D 等位基因的影响是否因 GNB3 T 单倍型的共同遗传而改变。这种多态性与α肾上腺素能激活增加和血浆肾素水平降低有关，并且在黑人群体中更为普遍。具体目标 3 将探索在黑人心力衰竭队列中使用混合连锁不平衡作图 (MALD)，该方法利用非洲和欧洲起源的基因组 DMA 的比较，以确定基因组学对重塑和心脏的明显种族差异的潜在贡献失败的结果。该提案将解决一个重要的临床问题，并将为指导年轻研究人员参与遗传学结果研究的方法提供理想的计划。