HERITAGE FAMILY STUDY, PHASE 4

描述（由申请人提供）：规律的体力活动与有利的心血管风险因素特征、较低的发病率和较低的过早死亡率相关。然而，在身体活动的生活方式所带来的益处方面存在个体差异。在遗产家庭研究的前几个阶段中，对这种现象进行了调查，其中来自214个核心家庭的742名黑人和白人，所有成年人，完成了标准化和全面监测的20周运动训练计划。有很大的个体间差异的反应性，但这种异质性不是随机分布的，因为有显着的家族相似性的危险因素的大小，运动计划的反应。这些反应的差异与许多候选基因有关。此外，广泛的数据分析，有可能确定几个数量性状基因座（QTL）的重要风险因素的反应。在这一更新期（第4阶段; 2005年至2010年），我们的主要目标是完成4个QTLs的定位克隆工作，心肺功能和血流动力学表型的反应，定期运动，解决他们的候选基因和等位基因变异，并在功能上确认它们。来自彭宁顿生物医学研究中心和华盛顿大学的研究人员正在提交一份修改后的申请，以继续过去12年来在追求拟议的定位克隆目标方面建立的密切合作。在HERITAGE家族研究的第4期中要检验的假设是，人类对定期运动的心肺适应性和血流动力学变化受至少4个QTL的调节。这些QTL中的两个已经产生了强候选基因：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适应性和运动心率表型QTL的定位克隆工作，即，QTL 3和QTL 4（特异性目标1）。此外，我们将继续进行体外研究，以表征与定期运动反应相关的SNP等位基因的功能特性（具体目标2）。这项研究将产生关于适应生物学和人类对定期运动的反应异质性的分子基础的独特数据。旨在了解为什么有些人从根本上比其他人更有可能从身体活动的生活方式中受益的研究非常重要，因为这种生活方式是所有国家和国际公共卫生当局推荐的。

DESCRIPTION (provided by applicant): 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 associated with 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 hemodynamic 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., QTL3 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.