Gene-Specific Responses to Exercise in Discordant Twins

描述(由申请者提供)：作为国家跑步者健康研究的一部分，我们已经确认了1350名跑步者有同卵双胞胎(MZ)。我们的招募经验表明，通过Runner的世界比赛参与计划，可以在全国范围内找到额外的3120名MZ双胞胎。在这些MZ双胞胎中，28%的人预计不适合剧烈运动(久坐不动，而不是每周跑步超过10英里)，否则有资格接受研究。我们建议采集400对不协调的MZ双胞胎的血液进行基因分型、详细的脂蛋白亚组分测量、临床体重以及近期(饮食记录)和长期(食物频率问卷)营养素摄入量，以测试基因是否影响脂蛋白和体重对剧烈运动的反应。分析假设，久坐的双胞胎(理论上)代表了活动双胞胎的体重和脂蛋白浓度，如果他或她久坐的话。在调整饮食后，我们将比较不同基因型别的同卵双胞胎脂蛋白和体重差异。候选基因将包括其他人已经确定的影响脂蛋白、体重、运动倾向或减轻脂蛋白对运动反应的SNPs。我们还将把双胞胎表型差异与SNPs和单倍型进行比较，连锁不平衡图表明，SNPs和单倍型表征了影响脂蛋白代谢的基因的大部分主要遗传变异。这些脂蛋白将包括使用梯度凝胶电泳法对高密度脂蛋白(HDL)和低密度脂蛋白(LDL)亚类进行详细测量。通过免疫亲和层析将高密度脂蛋白分离成同时含有载脂蛋白A-I和载脂蛋白A-II的颗粒(高密度脂蛋白(A-I带有A-II))和那些含有载脂蛋白A-I和不含载脂蛋白A-II的颗粒(高密度脂蛋白(A-I不含A-II))后，还将分析各个高密度脂蛋白亚类。 该设计既提供了横断面关联研究(大表型效应)和训练研究(控制基因型)的优点，又没有横断面关联研究的自我选择偏差或训练研究的小表型反应。我们第一次对35对MZ双胞胎进行的初步研究显示，在活动和久坐的双胞胎中，高密度脂蛋白-胆固醇的差异为5.2 mg/dL，体重差异为12磅。相比之下，最近的一项主要培训研究显示，经过20周的培训后，高密度脂蛋白胆固醇的平均水平仅有小幅上升(男性：L.1 mg/dL；女性：1.4 mg/dL)，体重也略有下降(男性：0.9磅；女性：0.4磅)。与训练研究相比，不协调双胞胎研究的更大效应规模将提供更大的统计能力来检测基因-环境相互作用。DNA样本将与其他机构共享，以交叉验证从培训研究或其他设计中确定的基因关联。

DESCRIPTION (provided by applicant): As part of the National Runners' Health Study, we have identified 1,350 runners who have an identical (MZ) twin. Our recruitment experience shows that an additional 3,120 MZ twins can be located nationally through Runner's World race participation program. Twenty-eight percent of these MZ twin pairs are expected to be discordant for vigorous exercise (sedentary versus running over 10 miles per week) and otherwise eligible for study. We propose to obtain blood for genotyping, detailed lipoprotein subfraction measurements, clinic weights, and proximal (diet record) and long-term (food frequency questionnaire) nutrient intakes in 400 discordant MZ twin pairs to test whether genes affect the lipoprotein and weight response to vigorous exercise. The analyses assume that the sedentary twin represents (theoretically) the body weight and lipoprotein concentrations of the active twin if he or she were sedentary. We will compare the co-twin lipoprotein and weight differences across genotypes after adjusting for diet. Candidate genes will include SNPs that have been identified by others to affect lipoproteins, weight, propensity to exercise, or that mitigate the responses of lipoproteins to exercise. We will also compare the co-twin phenotype differences to SNPs and haplotypes that linkage disequilibrium maps suggest characterize most of the major genetic variation for genes affecting lipoprotein metabolism. The lipoproteins will include detailed measurements of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) subclasses using gradient gel electrophoresis. The individual HDL subclasses will also be analyzed after separating the HDL by immunoaffinity chromatography into particles containing both apo A-I and apo A-II (HDL(A-I with A-II)) and those containing apo A-I and no apo A-II (HDL(A-I without A-II)). The design provides the advantages of both the cross-sectional association studies (large phenotypic effects) and the training studies (controlling for genotype) without the self-selection bias of cross-sectional association studies or the small phenotypic response of training studies. Our first pilot study of 35 pairs of MZ twins revealed a 5.2 mg/dL difference in HDL-cholesterol and a 12 pound weight difference between the active and sedentary twin. By comparison, a major recent training study produced only small average increases in HDL cholesterol (men:l.1 mg/dL; women:l.4 mg/dL) and small decreases in weight (men: 0.9 pounds; women: 0.4 pounds) after 20 weeks of training. The larger effect size of the discordant twin study will provide greater statistical power to detect gene-environment interactions than the training study. DNA samples will be shared with other institutions to cross-validate gene associations identified from training studies or other designs.