Exceptional Survival in Danish and Italian Families

描述(申请人提供)：我们将利用多中心长寿家庭研究(LLFS)，这是一个独特的研究人类长寿和健康老龄化的资源，以寻找与这些特征相关的遗传变异。在此期间，我们成功地招募了539个两代人家庭的4953个个体，并对其进行了广泛的表型鉴定，这些家庭展示了在上一代中表现出非凡生存的聚集性。只有不到1%的弗雷明翰心脏研究(FHS)家庭(粗略随机抽样的家庭)将达到LLFS要求的特殊生存的最低入学标准。因此，我们最不特殊的家庭比99%的弗雷明翰家庭表现出更多的聚集性，从而延长了非凡的寿命。此外，与FHS相比，儿童一代的主要老龄化疾病(包括糖尿病、慢性肺部疾病、外周动脉疾病)的发病率显著降低，并显示出明显更有利的健康老龄化量化指标，如血压、血脂、功能表现和认知指数。这些内表型在LLFS家族中比在FHS中表现出更大的聚集性(具有较高的遗传力)。因此，LLFS很可能极大地丰富了长寿和健康衰老内表型的任何基因变异的流行程度，从而提高了检测能力。最重要的是，与对无关个体的研究相比，LLFS的家系设计提供了额外的力量和分析机会来发现遗传影响，特别是关于稀有等位基因的研究。我们的具体目标是：1)通过分析储存样本上健康老龄化的生物标记物，继续进行表型鉴定，每年跟踪新的重大医疗和健康事件的受试者，并将Medicare(和丹麦同等标准)的疾病和利用数据与参考样本进行比较；2)使用GWAS识别与健康老龄化和例外生存相关的常见基因变体；3)通过靶向测序确定异常存活和健康衰老的罕见变量；以及4)通过涉及基因网络和途径的系统方法，更清楚地剖析异常存活和健康衰老的遗传架构，以更好地了解基因变量、暴露和协变量在内表型发展中的复杂相互作用。采取涉及临床医生、人口学家、遗传学家、流行病学家和计算科学家的多学科方法，我们建议利用已有的投资创建这个独特的队列，以加深我们对特殊生存和健康老龄化本质的理解。 公共卫生相关性：在参加LLFS的家庭中，异常长寿和健康老龄化的家庭非常丰富，从而使我们有独特的机会发现与这些特征的共同和罕见的遗传关联。这些关联不仅将显著增强我们对为什么有些人衰老得比其他人好得多的理解，而且还将导致对健康和不健康老龄化的预测以及潜在的疾病预防策略。

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.