Analysis of Coding Variants Associated with Age-Related Phenotypes

与年龄相关表型相关的编码变异分析

• 批准号: 8522762
• 负责人: Laura M Raffield
• 金额: $ 4.22万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522762
• 关键词: Adult; Affect; African American; Aging; Aging-Related Process; Area; Behavioral; Blindness; Blood Vessels; Bone Density; Brain; Calcified; Cardiovascular Diseases; Caring; Cerebrovascular Disorders; Characteristics; Code; Cohort Studies; Comorbidity; Complement 1q; Complex; Cytokine Receptors; DNA Sequence; Data; Data Set; Databases; Development; Diabetes Mellitus; Discipline; Disease; Elderly; Evaluation; Family; Family member; Gene Family; Genes; Genetic; Genetic Risk; Genetic Variation; Genotype; Goals; Heart; Human Genetics; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-18; Interleukin-6; Interleukins; Investigation; Knowledge; Lead; Life Style; Link; Magnetic Resonance Imaging; Measures; Medicine; Meta-Analysis; Metabolic; Metabolism; Methods; Mind; Mutation; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Physical Function; Plasma; Play; Process; Proteins; Research; Research Personnel; Risk; Role; Scientist; Stroke; Structure; Surveys; Technology; Testing; Training Programs; Tumor Necrosis Factor-alpha; United States; Variant; Vascular Diseases; Vascular calcification; adiponectin; age related; base; cardiovascular disorder risk; cognitive function; cohort; cytokine; exome; exome sequencing; experience; follow-up; forest; genetic variant; high risk; improved; interest; member; mortality; next generation sequencing; pandemic disease; public health relevance; receptor; receptor binding; tool; trait

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.

描述（由申请人提供）：衰老过程中的许多合并症，包括心血管疾病、认知能力下降和代谢失调，被认为受到遗传因素的显着影响。 2 型糖尿病 (T2D) 是一种影响美国 25% 以上 65 岁以上成年人的疾病，也被认为具有显着的遗传因素，患有 T2D 的人患与年龄相关的合并症的风险很高。常见和不常见的编码遗传变异可能在这些与年龄相关的合并症中发挥重要作用，该项目旨在阐明与衰老和死亡率的多种生物医学指标显着相关的编码变异。 Illumina(R) HumanExome BeadChips 包含超过 240,000 个编码变体，可对糖尿病心脏研究队列中的相关编码变体进行快速、全面的分析，该队列是一个针对 T2D 患者进行广泛表型分析的基于家庭的队列。我们最初的重点是 C1q 和肿瘤坏死因子 (TNF) 基因超家族。最近发现了该家族成员脂联素的罕见编码变异，该变异导致该蛋白质的血浆水平急剧降低，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，可能会导致与年龄相关的表型。与炎症相关的基因，例如细胞因子及其受体，也将受到特别关注，因为炎症过程是许多与年龄相关的疾病（包括 T2D）发病机制的关键。糖尿病心脏研究的外显子组芯片数据的有趣发现将在与衰老相关的其他队列中得到复制。拟议的研究将进一步促进我作为一名独立研究者的发展，并为我在将人类遗传学工具有意义地应用于衰老研究方面提供宝贵的经验。