Multicenter Study on Exceptional Survival in Families: The Long Life Family Study

描述（由申请人提供）：我们将利用多中心长寿家庭研究（LLFS），这是研究人类长寿和健康衰老的独特资源，寻找与这些特征相关的遗传变异。在当前阶段，我们成功地招募了539个两代家庭的4953个个体，并对其进行了广泛的表型分析，这些家庭在上一代中表现出异常生存的聚集性。在弗雷明汉心脏研究（FHS）中，只有不到1%的家庭（一个大致随机的家庭样本）符合LLFS所要求的特殊生存的最低入学标准。因此，我们最不例外的家庭比99%的弗雷明汉家庭表现出更多的长寿聚集性。此外，儿童一代在糖尿病、慢性肺病、外周动脉疾病等主要衰老疾病的发病率显著低于家庭家庭，在血压、血脂、功能表现和认知指标等健康衰老的定量指标上也明显优于家庭家庭。这些内表型在LLFS家族中比在FHS家族中表现出更大的聚集性（具有高遗传力）。因此，LLFS可能极大地增加了任何长寿和健康衰老内表型基因变异的患病率，从而提高了检测能力。最重要的是，LLFS的家族设计为发现遗传影响提供了额外的能力和分析机会，而不是在不相关个体的研究中，特别是在罕见的等位基因方面。我们的具体目标是：1)通过分析存储样本中健康衰老的生物标志物来继续进行表型分析，每年跟踪新的重大医疗和健康事件，并将医疗保险（和丹麦同等）疾病和利用数据与参考样本进行比较；2)利用GWAS识别健康衰老和特殊生存的常见遗传变异；3)通过靶向测序鉴定罕见变异，实现异常生存和健康衰老；4)通过涉及基因网络和通路的系统方法，更清楚地剖析异常生存和健康衰老的遗传结构，以更好地理解遗传变异、暴露和协变量之间复杂的相互作用。采用涉及临床医生、人口统计学家、遗传学家、流行病学家和计算科学家的多学科方法，我们建议利用已经在创建这一独特队列方面所做的投资，进一步加深我们对特殊生存和健康老龄化本质的理解。

DESCRIPTION (provided by applicant): We will exploit the multicenter Long Life Family Study (LLFS), a unique resource for research on human longevity and healthy aging, to find genetic variants associated with these traits. In the current period, we successfully enrolled and extensively phenotyped 4,953 individuals in 539 two-generational families that demonstrate clustering for exceptional survival in the upper generation. Fewer than 1% of the Framingham Heart Study (FHS) families (a roughly random sample of families) would meet the minimal entrance criteria for exceptional survival required in the LLFS. Thus our least exceptional families show more clustering for exceptional longevity than 99% of the Framingham families. Further, the children's generation have significantly lower rates of major diseases of aging including diabetes, chronic pulmonary disease, peripheral artery disease and show significantly more favorable profiles of quantitative mariners of healthy aging such as blood pressure, lipids, functional performance, and cognitive indices compared to FHS. These endophenotypes show greater clustering (with high heritability) in the LLFS familiesthan in FHS. Thus, LLFS has likely greatly enriched the prevalence of any gene variants for longevity and healthy aging endophenotypes, thereby increasing detection power. Most importantly, the family design of LLFS provides additional power and analytic opportunities to discover genetic influences than would be possible in a study of unrelated individuals, especially with regard to rare alleles. Our specific aims are to: 1) continue phenotyping by assaying biomarkers of healthy aging on stored samples, annually tracking subjects for new significant medical and health events, and comparing Medicare (and Danish equivalent) disease and utilization data with reference samples; 2) identiy common genetic variants for healthy aging and excepional survival using GWAS; 3) identify rare variants for exceptional survival and healthy aging by targeted sequencing; and 4) more clearly dissect the genetic architecture of exceptional survival an healthy aging through a systems approach involving genet networks and pathways, to better understand the complex interplay between genetic variants, exposures, and covariates in the development of endophenotypes. Taking a multidisciplinary approach involving clinicians, demographers, geneticists, epidemiologists, and computational scientists, we propose to capitalize on the investments already made in creating this unique cohort to further our understanding of the nature of exceptional survival and healthy aging. PUBLIC HEALTH RELEVANCE: Exceptional longevity and healthy aging are highly enriched in the families enrolled in the LLFS thus allowing us a unique opportunity to discover both common and rare genetic associations with these traits. Such associations will not only markedly enhance our understanding of why some people age so much better than others, but will also lead to enhanced prognostication for healthy and unhealthy aging and potentially disease prevention strategies.