Analysis of Coding Variants Associated with Age-Related Phenotypes

描述(由申请人提供)：许多衰老过程的共病，包括心血管疾病、认知功能减退和代谢失调，被认为受到遗传因素的显著影响。2型糖尿病(T2D)是一种在美国65岁以上的成年人中影响超过25%的疾病，也被认为是一个重要的遗传成分，患有T2D的人患上与年龄相关的合并症的风险很高。常见和不常见的编码基因变异可能在这些与年龄相关的合并症中发挥重要作用，本项目旨在阐明与多种生物医学措施显著相关的编码变异，这些生物医学指标具有衰老和死亡率的特点。Illumina(R)HumanExome BeadChips包括超过240,000种编码变体，将允许对糖尿病心脏研究队列中的相关编码变体进行快速和全面的分析。糖尿病心脏研究队列是一个广泛表型的以家族为基础的队列，为T2D患者丰富。我们最初的重点将放在C1q和肿瘤坏死因子超家族基因上。最近发现了该家族成员脂联素中不常见的编码变体，它导致该蛋白的血浆水平急剧下降，我们假设其他C1q/TNF超家族成员的编码变体可能与年龄相关的表型有关，这些超家族成员在代谢、炎症和其他过程中扮演着不同的角色。与炎症相关的基因，如细胞因子及其受体，也将特别令人感兴趣，因为炎症过程是许多与年龄相关的疾病发病的关键，包括T2D。来自糖尿病心脏研究的Exome芯片数据的有趣发现将在其他与衰老相关的队列中复制。这项拟议的研究将进一步促进我作为一名独立研究员的发展，并在有意义地将人类遗传学工具应用于衰老研究方面给予我宝贵的经验。

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.