PACIFIC GENETIC EPIDEMIOLOGIC STUDY ON AGING

描述：(应用摘要)流行病学、家族性和双胞胎 研究表明，很大比例的表型变异在 长寿和机能能力是遗传的。一种可能的解释是 对代谢途径有重要影响的单基因的多态性 可能与一些慢性疾病的潜在发病机制有关 条件和老化过程同时进行。为了探索这一假设， 以及衰老遗传学的其他领域，我们建议启动和 开发一个新的遗传网络[太平洋遗传(PacGen)网络] 遗传学、流行病学、老年病学、生物统计学和 夏威夷大学库阿基尼医学中心的环境科学， 女王医学中心、斯坦福大学和太平洋健康研究中心 研究所。该网络将以火奴鲁鲁现有要素为基础 心脏计划(HHP)，一项针对老年日裔美国人和 家族性血压计划--一项关于糖尿病遗传学的多中心研究 高血压。将规划和实施全面的遗传流行病学 利用候选基因/遗传关联分析研究衰老 设计。在第一阶段，我们将展示此网络的能力 调查与长寿和维持健康相关的遗传因素 以总体为基础的样本的功能能力。利用单核苷酸 与表型数据连锁的多态(SNPs)和现有的HHP DNA样本 根据35年来衡量的握力和其他因素，我们将确定5 6个线粒体和核候选基因的高频SNPs (30个SNPs)。候选基因将根据生物知识进行选择 家族性血压计划--一项关于糖尿病遗传学的多中心研究 高血压。将规划和实施全面的遗传流行病学 利用候选基因/遗传关联分析研究衰老 设计。在第一阶段，我们将展示此网络的能力 调查与长寿和维持健康相关的遗传因素 以总体为基础的样本的功能能力。利用单核苷酸 与表型数据连锁的多态(SNPs)和现有的HHP DNA样本 根据35年来衡量的握力和其他因素，我们将确定5 6个线粒体和核候选基因的高频SNPs (30个SNPs)。候选基因将根据生物知识进行选择 将它们与能量平衡和/或产生/排毒联系起来 氧自由基，尤其是线粒体遗传变异。基因分型 将为30个SNP中的每一个开发检测方法，每个SNP将被 对1997-1999年间检查的1,953名老年人进行了基因分型。我们会 还招募了100名HHP队列的家庭成员(年龄55岁和 上图)。在该样本中，我们将试行测试表型措施，包括 为将来的研究提供基于性能的身体机能测量。利用 HPP数据我们将探索创新的分析方法，如分位数 处理人口变化率数据和数据的回归方法 生存表型及其相关基因。在这第一次 阶段PacGen网络将制定并提交更多建议 综合遗传流行病学研究(第二阶段)。

DESCRIPTION: (Abstract from application) Epidemiological, family, and twin studies suggest that a substantial proportion of the phenotypic variation in longevity and functional ability is genetic. One possible explanation is that polymorphisms of single genes with important effects on a metabolic pathway may contribute to the underlying pathogenesis of a number of chronic conditions and the aging process simultaneously. To explore this hypothesis, as well as other areas in the genetics of aging, we propose to initiate and develop a new genetic network [the Pacific Genetic (PacGen) Network] of experts in genetics, epidemiology, geriatrics, biostatistics and environmental science from the University of Hawaii, Kuakini Medical Center, Queen's Medical Center, Stanford University and the Pacific Health Research Institute. The Network will be based on existing elements of the Honolulu Heart Program (HHP), an epidemiologic study of elderly Japanese Americans and the Family Blood Pressure Program, a multi-center study of the genetics of hypertension. It will plan and carryout comprehensive genetic epidemiologic studies in aging utilizing candidate gene/genetic association analysis designs. In Phase I, we will demonstrate the ability of this network to investigate genetic factors associated with longevity and maintenance of functional ability in a population based sample. Utilizing single nucleotide polymorphisms (SNPs) and existing HHP DNA samples linked with phenotypic data on grip strength and other factors measured over 35 years, we will identify 5 high frequency SNPs in each of 6 mitochondrial and nuclear candidate genes (30 SNPs). Candidate genes will be selected based on biologic knowledge the Family Blood Pressure Program, a multi-center study of the genetics of hypertension. It will plan and carryout comprehensive genetic epidemiologic studies in aging utilizing candidate gene/genetic association analysis designs. In Phase I, we will demonstrate the ability of this network to investigate genetic factors associated with longevity and maintenance of functional ability in a population based sample. Utilizing single nucleotide polymorphisms (SNPs) and existing HHP DNA samples linked with phenotypic data on grip strength and other factors measured over 35 years, we will identify 5 high frequency SNPs in each of 6 mitochondrial and nuclear candidate genes (30 SNPs). Candidate genes will be selected based on biologic knowledge linking them with energy homeostasis and/or the generation/detoxification of oxygen free radicals, especially mitochondrial genetic variation. Genotyping assays will be developed for each of the 30 SNPs and each SNP will be genotyped in the 1,953 elderly individuals examined in 1997-1999. We will also recruit a sample of 100 family members of the HHP cohort (ages 55 and above). In that sample we will pilot test phenotypic measures including performance based measures of physical function for future studies. Utilizing HPP data we will explore innovative analytical approaches such as quantile regression methods for dealing with population rate of change data and survival phenotypes and the genes associated with them. During this first phase the PacGen Network will develop and submit proposals for more comprehensive genetic epidemiologic studies (Phase II).