HERITAGE FAMILY STUDY, PHASE 4

传统家庭研究，第 4 阶段

• 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
• 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

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.

规律的体力活动与良好的心血管危险因素相关， 降低发病率和过早死亡率。然而，在这方面观察到个体差异。 积极锻炼身体的生活方式所带来的益处。这一现象在《 在遗产家庭研究的前几个阶段，来自214个核心家庭的742名黑人和白人， 所有的成年人，完成了一个标准化的和全面监测的20周运动训练计划。有 反应性的个体间差异很大，但这种异质性不是随机分布的， 在对运动的危险因素反应的程度上有显著的家族相似性 程序.这些反应差异与许多候选基因有关。此外，委员会认为， 对数据的广泛分析使得有可能确定几个数量性状基因座（QTL）， 应对重大风险因素。在这一更新阶段（第四阶段; 2005年至2010年），我们的主要目标是 总结了心肺适应性反应的四个QTL的定位克隆工作， 血液动力学表型定期运动，以解决他们的候选基因， 等位基因变体，并在功能上确认它们。来自彭宁顿生物医学中心的研究人员 研究中心和华盛顿大学正在提交一份修改后的申请， 过去12年来，在实现拟议的定位克隆目标方面建立了密切合作。的 在HERITAGE家族研究的第4阶段中要检验的假设是， 运动对血液动力学的影响受至少4个QTL的调控。两 这些QTL已经产生了强的候选基因：肌联蛋白（TTN; QTL 1）和驱动蛋白5 B（KIF 5 B; QTL 2）。我们 建议完成另外两个心肺健康QTL的定位克隆工作， 运动心率表型，即，QTLs和QTL 4（特定目标1）。此外，我们将继续 正在进行的体外研究，以表征已确定的SNP的等位基因的功能特性 与对定期运动的反应有关（具体目标2）。这项研究将产生独特的数据 关于适应生物学和人类反应异质性的分子基础 定期锻炼。研究旨在了解为什么有些人从根本上更有可能 从身体活动的生活方式比其他人受益是非常重要的，因为这样的生活方式是推荐的 所有国家和国际公共卫生当局。