HERITAGE FAMILY STUDY, PHASE 4

传统家庭研究，第 4 阶段

基本信息

批准号：
7340187
负责人：
Tuomo Rankinen
金额：
$ 66.82万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340187
关键词：
Adult Alleles Antithymoglobulin Area Biological Assay Biology Biomedical Research Candidate Disease Gene Code Collaborations Complex Computer Simulation DNA Sequence Data Data Analyses Databases Death Rate Electrophoretic Mobility Shift Assay Elements Exercise Family Family Study Functional RNA Gene Mutation Genes Genetic Heterogeneity Genetic Variation Genomics Goals Haplotypes Heart Rate Heterogeneity Human In Vitro Individual Differences International Intervention Introns Kinesin Life Style Link Lod Score Low Prevalence Luciferases Maps Measurement Messenger RNA Microsatellite Repeats Molecular Monitor Morbidity - disease rate Mutation Noise Nuclear Family Numbers Other Working Groups Phase Phenotype Physical activity Process Promoter Regions Property Prostaglandins A Proteins Public Health Quantitative Trait Loci Research Research Design Research Personnel Resources Risk Factors Scanning Screening procedure Signal Transduction Single Nucleotide Polymorphism Subgroup Terminator Codon Testing Training Training Programs Trees Universities Untranslated Regions Variant Washington Week authority base cardiovascular risk factor cohort connectin design experience fitness gene discovery genetic linkage analysis genome-wide linkage hemodynamics novel optimism positional cloning programs promoter protein structure response success tool trait

项目摘要

Regular physical activity is associated with a favorable cardiovascular risk factor profile, a lower prevalence of morbidities and reduced premature death rates. However, individual differences are observed in the magnitude of benefits derived from a physically active lifestyle. This phenomenon was investigated in the previous phases of the HERITAGE Family Study in which 742 Blacks and Whites from 214 nuclear families, all adults, completed a standardized and fully monitored 20-week exercise training program. There were large inter-individual differences in responsiveness but this heterogeneity was not randomly distributed, as there was significant familial resemblance in the magnitude of the risk factor responses to the exercise program. These differences in response have been associatedwith a number of candidate genes. Moreover, extensive analyses of the data have made it possible to identify several quantitative trait loci (QTLs) for the responses in important risk factors. In this renewal period (Phase 4; 2005 to 2010), our main goal is to conclude the positional cloning efforts of four QTLs for the response of cardiorespiratory fitness and hemodynamic phenotypes to regular exercise, to resolve them in terms of candidate genes and allelic variants, and to functionally confirm them. Investigators from the Pennington Biomedical Research Center and from Washington University are submitting a single revised application to continue the close collaboration established over the last 12 years in pursuing the proposed positional cloning goals. The hypothesis to be tested in Phase 4 of the HERITAGE Family Study is that human cardiorespiratory fitness and hemodvnamic changes in response to regular exercise are regulated by a minimum of four QTLs. Two of these QTLs have yielded strong candidate genes: titin (TTN; QTL1), and kinesin 5B (KIF5B; QTL2). We propose to finalize the positional cloning efforts of two other QTLs for cardiorespiratory fitness as well as exercise heart rate phenotypes, i.e., QTLS and QTL4 (Specific Aim1). Furthermore, we will continue the ongoing in vitro studies to characterize the functional properties of the alleles of the SNPs that have been associated with the response to regular exercise (Specific Aim 2). This research will generate unique data concerning the biology of adaptation and the molecular basis of human heterogeneity in the responsiveness to regular exercise. Studies designed to understand why some people are fundamentally more likely to benefit from a physically active lifestyle than others are very important as such a lifestyle is recommended by all national and international public health authorities.

定期体育锻炼与有利的心血管危险因素有关，患病率较低病态和过早死亡率的降低。但是，在从身体上活跃的生活方式衍生出的好处。这种现象在遗产家庭研究的先前阶段，其中有214个核家庭的742个黑人和白人，所有成年人都完成了一项标准化且全面监控的20周运动训练计划。有响应性的个体间差异很大，但这种异质性不是随机分布的，因为危险因素对运动的危险因素的大小有很大的相似之处程序。这些反应的差异与许多候选基因有关。而且，对数据的广泛分析使得可以确定几个定量性状基因座（QTL）重要的风险因素的反应。在这个续签时期（第4阶段； 2005年至2010年），我们的主要目标是总结了四个QTL的位置克隆努力，以响应心肺适应性和血液动力学表型定期运动，以候选基因和等位基因变体，并在功能上确认它们。彭宁顿生物医学的调查人员研究中心和华盛顿大学正在提交一个修订的申请，以继续在过去的12年中，建立了紧密的合作，以追求拟议的位置克隆目标。这在遗产家庭研究的第4阶段要检验的假设是人类心肺健康响应定期运动的响应血液动态变化至少四个QTL。二在这些QTL中，产生了强大的候选基因：TITIN（TTN; QTL1）和驱动蛋白5B（KIF5B; QTL2）。我们建议最终确定其他两个QTL的位置克隆工作，以进行心肺健康以及运动心率表型，即QTL和QTL4（特定AIM1）。此外，我们将继续正在进行的体外研究以表征SNP等位基因的功能特性与定期运动的响应有关（特定目标2）。这项研究将产生独特的数据关于适应的生物学和人类异质性的分子基础定期运动。研究旨在了解为什么有些人从根本上更有可能从某种身体上活跃的生活方式中受益于其他人非常重要，因为建议这种生活方式所有国家和国际公共卫生当局。