HERITAGE FAMILY STUDY, PHASE 4: THE GENOMICS CENTER

描述(由申请人提供)：有规律的体力活动与良好的心血管危险因素特征、较低的发病率和较低的过早死亡率相关。然而，从体育活动的生活方式中获得的益处的大小存在个体差异。这一现象在遗产家庭研究的前几个阶段进行了调查，在该研究中，来自214个核心家庭的742名黑人和白人，全部是成年人，完成了为期20周的标准化和全面监控的运动训练计划。个体间的反应性有很大的差异，但这种异质性不是随机分布的，因为对运动计划的危险因素反应的大小存在显著的家族相似性。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对重要风险因素的反应的几个数量性状基因座(QTL)。在这一更新阶段(阶段4；2005-2010)，我们的主要目标是总结四个影响心肺功能和血流动力学表型对常规运动的反应的QTL的位置克隆工作，从候选基因和等位基因变异的角度来解决它们，并从功能上证实它们。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年来在追求拟议的位置克隆目标方面建立的密切合作。在传统家族研究的第四阶段将检验的假设是，人类对定期运动的心肺适应性和血流动力学变化至少受四个QTL调控。这些QTL中有两个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与心肺功能和运动心率表型有关的QTL的位置克隆工作，即QTL3和QTL4(特异性Aim1)。此外，我们将继续正在进行的体外研究，以表征与常规运动反应(特定目标2)相关的SNPs等位基因的功能特性。这项研究将产生关于适应生物学和人类对常规运动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受益于体育活动的生活方式的研究非常重要，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.