Gene-Specific Responses to Exercise in Discordant Twins

描述（由申请人提供）：作为国家跑步者健康研究的一部分，我们已经确定了1350名拥有同卵双胞胎（MZ）的跑步者。我们的招募经验表明，通过参加世界跑者比赛项目，可以在全国范围内增加3120名MZ双胞胎。在这些MZ双胞胎中，28%的人在剧烈运动（久坐与每周跑步超过10英里）方面不一致，在其他方面也符合研究条件。我们建议对400对不一致的MZ双胞胎进行血液基因分型、详细的脂蛋白亚组分测量、临床体重、近端（饮食记录）和长期（食物频率问卷）营养摄入，以测试基因是否影响剧烈运动对脂蛋白和体重的反应。分析假设久坐双胞胎代表（理论上）活跃双胞胎的体重和脂蛋白浓度，如果他或她久坐。在调整饮食后，我们将比较不同基因型的双胎脂蛋白和体重差异。候选基因将包括已被其他人鉴定的影响脂蛋白、体重、运动倾向或减轻脂蛋白对运动反应的snp。我们还将比较同卵双生的表型差异与单核苷酸多态性和单倍型，连锁不平衡图谱显示了影响脂蛋白代谢基因的大多数主要遗传变异的特征。脂蛋白将包括使用梯度凝胶电泳的高密度脂蛋白（HDL）和低密度脂蛋白（LDL）亚类的详细测量。通过免疫亲和层析将HDL分离为含有载脂蛋白A-I和载脂蛋白A-II的颗粒（HDL(A-I带A-II)）和含有载脂蛋白A-I和不载脂蛋白A-II的颗粒（HDL(A-I不带A-II)）后，还将分析单个HDL亚类。

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.