HERITAGE FAMILY STUDY, PHASE 4

有规律的体力活动与有利的心血管危险因素相关，患病率较低 减少发病率和降低过早死亡率。然而，个体差异在 从身体活动的生活方式中获得的巨大好处。这一现象已在 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， 所有成年人都完成了为期20周的标准化和全面监控的运动训练计划。有几个 个体间的反应差异很大，但这种异质性并不是随机分布的，因为 在对运动的危险因素反应的大小上有显著的家族相似性。 程序。这些反应上的差异与许多候选基因有关。此外， 对数据的广泛分析使人们有可能识别出几个数量性状基因座(QTL) 对重要风险因素的反应。在这一更新期间(第四阶段；2005年至2010年)，我们的主要目标是 总结了影响心肺适应性反应的四个QTL的位置克隆努力 血流动力学表型的规律运动，以解决他们的候选基因和 等位基因变异，并从功能上确认它们。彭宁顿生物医学中心的调查人员 研究中心和华盛顿大学提交了一份修订后的申请，以继续 在过去12年中，在实现拟议的位置克隆目标方面建立了密切的合作。这个 在传统家族研究的第四阶段将检验的假设是，人类的心肺健康 而规律运动引起的血液动力学变化至少受四个QTL的调控。二 在这些QTL中，产生了很强的候选基因：Titin(TTN；QTL1)和kinesin 5B(KIF5B；QTL2)。我们 建议完成另外两个心肺功能QTL的位置克隆工作，以及 运动心率表型，即QTL和QTL4(特异性Aim1)。此外，我们将继续 正在进行的体外研究，以表征SNPs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 关于适应的生物学和人类反应异质性的分子基础 有规律的锻炼。旨在了解为什么有些人从根本上更有可能 受益于身体活动的生活方式比其他人更重要，因为这样的生活方式是由 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.