HERITAGE FAMILY STUDY, PHASE 4

定期进行体力活动与良好的心血管危险因素相关，患病率较低 发病率并降低过早死亡率。然而，观察到个体差异 身体活跃的生活方式带来的好处的大小。这一现象在 HERITAGE 家庭研究的前几个阶段，其中来自 214 个核心家庭的 742 名黑人和白人， 所有成年人都完成了标准化且全面监控的 20 周运动训练计划。有 反应能力存在很大的个体差异，但这种异质性并不是随机分布的，因为 演习中风险因素反应的程度具有显着的家族相似性 程序。这些反应差异与许多候选基因有关。而且， 对数据的广泛分析使得确定几个数量性状位点（QTL）成为可能。 对重要危险因素的反应。在这个更新时期（第四阶段；2005年至2010年），我们的主要目标是 总结了四个 QTL 对心肺健康反应的位置克隆工作，以及 血流动力学表型到定期运动，以候选基因和 等位基因变异，并在功能上确认它们。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，以继续 过去 12 年来为实现拟议的定位克隆目标而建立的密切合作。的 HERITAGE 系列研究第 4 阶段要测试的假设是，人类心肺健康 定期运动引起的血液动力学变化至少受四个 QTL 的调节。两个 这些 QTL 产生了强大的候选基因：肌联蛋白（TTN；QTL1）和驱动蛋白 5B（KIF5B；QTL2）。我们 建议完成另外两个用于心肺健康以及 运动心率表型，即 QTLS 和 QTL4（具体目标 1）。此外，我们还将继续 正在进行的体外研究，以表征已被证实的 SNP 等位基因的功能特性 与对定期运动的反应相关（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 从身体活跃的生活方式中受益比其他人更重要，因为这种生活方式是由 所有国家和国际公共卫生当局。

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.