HERITAGE-GENETICS, RESPONSE TO EXERCISE, RISK FACTORS-3

HERITAGE家族研究的目的是记录耐力训练对心血管和代谢的反应，以及遗传因素对心血管疾病（CVD）伴随反应的贡献，以及2型糖尿病的危险因素。在第一阶段（1992-1997），从218个家庭招募了855名久坐不动的受试者，742名受试者（来自99个家庭的483名白人，来自105个家庭的259名黑人）完成了一个标准化的20周运动训练项目。在第二阶段（1997-2001），进行了一系列关于久坐状态和训练反应中心肺耐力决定因素、心血管疾病和2型糖尿病风险因素的非遗传研究。遗传分析的重点是确定遗传水平，检测父系或母系效应、主要基因效应和分离模式。一组候选基因被分型用于关联和连锁研究。对心肺耐力、心血管疾病和2型糖尿病危险因素的训练反应进行全基因组扫描。建议的第三阶段围绕五个具体目标组织。首先，将调查与训练相关的主要心血管疾病危险因素变化的遗传流行病学问题，特别强调黑人和白人的差异。其次，基因和突变的搜索将继续利用四种策略：扩展全基因组扫描，包括靶向密集snp定位，使用SAGE扩展骨骼肌基因表达研究，使用AFLP技术和使用新的统计方法，如多元连锁方法，亚组分析和全基因组连锁测试。第三，将使用LONGMOD研究胰岛素敏感性、胰岛素分泌和葡萄糖有效性的遗传和非遗传决定因素，LONGMOD是MINMOD的扩展，目前正在开发中，以更有效地模拟纵向数据。第四，将研究目标心血管疾病危险因素的非遗传决定因素及其对耐力训练的反应，重点是黑白差异。第五，我们将评估在密切监督下的20周定期运动是否对习惯性身体活动水平和健康状况有任何长期影响。HERITAGE家族研究第三阶段的研究结果将提供关于运动生活方式的益处以及黑人和白人高反应和低反应表型的决定因素的独特信息。本申请由彭宁顿生物医学研究中心提交，该中心也是遗产联盟协调中心。

The aim of the HERITAGE Family Study is to document the cardiovascular and metabolic responses to endurance training, and the contribution of genetic factors to the concomitant response of cardiovascular disease (CVD), and type 2 diabetes risk factors. In Phase 1 (1992-1997), 855 sedentary subjects from 218 families were recruited and 742 subjects (483 Whites from 99 families, 259 Blacks from 105 families) completed a standardized 20-week exercise-training program. During Phase 2 (1997-2001), a series of non-genetic studies on determinants of cardiorespiratory endurance, and CVD and type 2 diabetes risk factors in the sedentary state and in the response to training were undertaken. Genetic analyses focused on the determination of the heritability levels, and testing for paternal or maternal effects, major gene effects and segregation patterns. A panel of candidate genes was typed for association and linkage studies. A genome-wide scan was performed for the training response of cardiorespiratory endurance and CVD and type 2 diabetes risk factors. The proposed Phase 3 is organized around five specific aims. First, genetic epidemiology questions pertaining to training-related changes in major CVD risk factors will be investigated with special emphasis on Black and White differences. Second, the search for genes and mutations will continue utilizing four strategies: extension of the genome-wide scan including targeted dense SNPs mapping, extension of the skeletal muscle gene expression studies with SAGE, use of the AFLP technique and use of novel statistical methods such as multivariate linkage methods, subgroup analyses, and total genome-wide linkage tests. Third, the genetic and non-genetic determinants of insulin sensitivity, insulin secretion and glucose effectiveness in response to training will be investigated using LONGMOD, an extension of MINMOD currently in development to model longitudinal data more efficiently. Fourth, the nongenetic determinants of the targeted CVD risk factors and their responses to endurance training will be investigated, with emphasis on Black and White differences. Fifth, we will assess whether a closely supervised 20-week period of regular exercise had any long-term effects on habitual physical activity levels and health status. The findings from Phase 3 of the HERITAGE Family Study will provide unique information on the benefits of a physically active lifestyle and on the determinants of the high and low response phenotypes in Blacks and Whites. This application is submitted from the Pennington Biomedical Research Center which also serves as the HERITAGE Consortium Coordinating Center.