Analysis of Coding Variants Associated with Age-Related Phenotypes

描述（由申请人提供）：许多衰老过程的合并症，包括心血管疾病、认知能力下降和代谢失调，被认为是受遗传因素显著影响的。2型糖尿病（T2D）是一种影响美国超过25% 65岁以上成年人的疾病，也被认为具有重要的遗传成分，并且患有T2D的个体具有与年龄相关的合并症的高风险。常见和不常见的编码遗传变异可能在这些与年龄相关的共病中发挥重要作用，本项目旨在阐明与衰老和死亡率特征的广泛生物医学指标显著相关的编码变异。Illumina(R) HumanExome BeadChips，包括超过24万个编码变体，将允许在糖尿病心脏研究队列中快速和全面地分析相关编码变体，这是一个广泛表型的基于家族的队列，丰富了T2D患者。我们最初的重点将放在C1q和肿瘤坏死因子（TNF）基因超家族上。该家族成员脂联素中不常见的编码变异最近被发现导致血浆中该蛋白水平急剧降低，我们假设其他C1q/TNF超家族成员的编码变异在代谢、炎症和其他过程中具有不同的作用，可能有助于年龄相关的表型。与炎症相关的基因，如细胞因子及其受体，也将特别感兴趣，因为炎症过程是许多年龄相关疾病（包括T2D）发病的关键。来自糖尿病心脏研究的外显子组芯片数据的有趣发现将在其他与衰老相关的队列中得到复制。这项研究将进一步促进我作为一名独立研究者的发展，并为我在人类遗传学工具在衰老研究中的有意义应用提供宝贵的经验。

DESCRIPTION (provided by applicant): Many comorbidities of the aging process, including cardiovascular disease, cognitive decline, and metabolic dysregulation, are thought to be significantly influenced by genetic factors. Type 2 diabetes (T2D), a disease which affects more than 25% of adults over age 65 in the United States, is also thought to have a significant genetic component, and individuals with T2D are at high risk for age-related comorbidities. Common and uncommon coding genetic variants may play a significant role in these age-related comorbidities, and this project aims to elucidate coding variants which are significantly associated with a wide range of biomedical measures characteristic of aging and with mortality. Illumina(R) HumanExome BeadChips, which include over 240,000 coding variants, will allow rapid and comprehensive analysis of relevant coding variants in the Diabetes Heart Study cohort, an extensively phenotyped family-based cohort enriched for patients with T2D. Our initial focus will be on the C1q and tumor necrosis factor (TNF) superfamily of genes. Uncommon coding variants in a member of this family, adiponectin, which lead to a dramatic reduction in plasma levels of this protein have recently been discovered, and we hypothesize that coding variants in other C1q/TNF superfamily members, which have diverse roles in metabolism, inflammation, and other processes, may contribute to age-related phenotypes. Genes related to inflammation, such as cytokines and their receptors, will also be of particular interest, as inflammatory processes are key to the pathogenesis of many age-related diseases, including T2D. Interesting findings from the Exome Chip data from the Diabetes Heart Study will be replicated in other cohorts relevant to aging. The proposed research will further my development as an independent investigator and give me valuable experience in the meaningful application of human genetics tools to aging research.