HERITAGE FAMILY STUDY, PHASE 4

描述（由申请人提供）：有规律的身体活动与良好的心血管危险因素、较低的发病率和降低的过早死亡率相关。然而，从积极运动的生活方式中获得的益处的大小可以观察到个体差异。这一现象在HERITAGE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名黑人和白人成年人完成了一项标准化的、全面监控的20周运动训练计划。在反应性方面存在很大的个体间差异，但这种异质性并不是随机分布的，因为对锻炼计划的风险因素反应的大小存在显著的家族相似性。这些反应的差异与许多候选基因有关。此外，通过对数据的广泛分析，可以确定几个数量性状位点（qtl）对重要危险因素的反应。在这个更新期（第4期；2005 - 2010），我们的主要目标是完成四个qtl的定位克隆工作，这些qtl与心肺适应性和血流动力学表型对定期运动的反应有关，并根据候选基因和等位基因变异对它们进行解析，并对它们进行功能确认。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，继续在过去12年里建立的密切合作，以追求拟议的位置克隆目标。在HERITAGE家族研究的第四阶段测试的假设是，人类心肺健康和血液动力学变化对定期运动的反应是由至少四个qtl调节的。其中两个qtl已经产生了强大的候选基因：titin （TTN; QTL1）和kinesin 5B （KIF5B; QTL2）。我们建议完成另外两个与心肺适应性和运动心率表型相关的QTL3和QTL4 （Specific Aim1）的定位克隆工作。此外，我们将继续进行正在进行的体外研究，以表征与定期运动反应相关的snp等位基因的功能特性（Specific Aim 2）。这项研究将产生关于适应的生物学和人类对定期运动反应的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积极运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.