Understanding the role of ApoE2 in longevity and age-related diseases and conditions using 500,000 UK Biobank participants

利用 500,000 名英国生物银行参与者了解 ApoE2 在长寿和年龄相关疾病和病症中的作用

• 批准号: 9768309
• 负责人: Chia-Ling Kuo
• 金额: $ 16.01万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768309
• 关键词: Adverse effects; Age related macular degeneration; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Applications Grants; Behavioral; Biochemical Markers; Bioinformatics; Biological; Biological Assay; Biological Markers; Cardiovascular Diseases; Caucasians; Chronic Disease; Clinical; Computerized Medical Record; Data; Data Analyses; Data Sources; Dementia; Detection; Disease; Disease Progression; Environment; Environmental Risk Factor; Expression Profiling; Favorable Clinical Outcome; Frequencies; Genes; Genetic; Genomics; Genotype; Geriatrics; Goals; Grant; Health; Hypertriglyceridemia; Incidence; Intervention; Kidney Diseases; Link; Longevity; Macular degeneration; Malignant Neoplasms; Maps; Mediating; Onset of illness; Outcome; Participant; Pathway Analysis; Pathway interactions; Phenotype; Physical activity; Population; Protein Isoforms; Records; Renal function; Reporting; Risk Factors; Role; Sample Size; Sampling; Single Nucleotide Polymorphism; Time; Tissues; Variant; Work; age related; aged; base; biobank; cardiovascular risk factor; cohort; experience; follow-up; gene interaction; genetic epidemiology; genetic variant; genome-wide; healthy aging; insight; medical specialties; phenotypic data; protective effect; trait

ApoE2 is associated with reduced incidence of Alzheimer’s Disease and with increased longevity. However, possibly adverse effects have also been reported on renal disease and macular degeneration. We hypothesize that the relationships between ApoE2 and age-related phenotypes are influenced by physical and behavioral factors, biochemical markers (biomarker), and genetic variants. Aging is by far the major risk factor for most of chronic diseases. To date, we have discovered many biological pathways of aging that appear to be shared by chronic diseases. Targeting the pathways from ApoE to aging and chronic diseases with consistent effects could result in overall highly favorable clinical outcomes. In this project, we aim to use the existing 500,000 UK Biobank (UKB) participants to identify ApoE2-associated phenotypes and characterize the effects of ApoE variants and their interactions. The UKB sample includes 217,000 subjects aged 60 to 73 at baseline, with 10 years of clinical records follow-up. The identified associations will be investigated for the underlying mechanisms using physical and behavioral factors, pathways associated with ApoE2-interacting genetic variants, and biomarkers that are established risk factors for cardiovascular diseases, cancers, kidney function and other outcomes. The UKB data is the largest data source of its kind, with rich genetic and phenotypic data that includes electronic medical records and will soon include over 30 biomarker assays. This empowers the detection of smaller effect sizes and offers the opportunity of analyzing multiple traits at the same time, in particular searching for gene-environment and gene-gene interactions with ApoE2. We are able to study the roles of environmental factors and biomarkers in the relationships between ApoE2 and age-related phenotypes and conduct a genome-wide gene-gene interaction study to identify ApoE2-interacting variants. These variants will be mapped to genes using both positional and functional information, including eQTL data to investigate the tissue-specific expression profiles for identified variants. Following that, gene-based and pathway (gene- set) analyses will be performed to gain biological insights. Our team has specialties in statistical genetics, genetic epidemiology, bioinformatics, genetics, and clinical geriatrics and includes leaders in this field with experience leading genomic analyses in aging cohorts. The proposed work builds on our recent analysis of parental longevity in UKB, which added 24 new variants to the previously proven associations with ApoE status.1 The long term goal of this project is to clarify positive and negative associations with health outcomes and to understand the relationships between ApoE2 and age-related phenotypes. By integrating the results across age-related phenotypes, we expect to clarify the positive and negative correlates of ApoE2 and identify pathways to target with potential interventions to ultimately promote healthy aging.

APOE2与阿尔茨海默氏病的发病率降低以及寿命增加有关。然而， 可能还报道了对肾脏疾病和黄斑变性的不利影响。我们假设 APOE2与年龄相关表型之间的关系受到身体和行为的影响 因素，生化标记（生物标志物）和遗传变异。到目前为止，衰老是大多数人的主要危险因素 慢性疾病。迄今为止，我们发现了许多衰老的生物学途径，这些途径似乎是由 慢性疾病。针对从APOE到衰老和具有一致效果的慢性疾病的途径 可能导致总体高度有利的临床结果。在这个项目中，我们旨在使用现有的500,000英国 生物库（UKB）参与者识别与APOE2相关的表型并表征APOE的影响 变体及其相互作用。 UKB样本包括217,000名基线时60至73岁的受试者，有10名 多年的临床记录随访。确定的协会将进行基础 使用物理和行为因素的机制，与APOE2相互作用相关的途径 是心血管疾病，癌症，肾功能的变体和生物标志物 和其他结果。 UKB数据是同类数据的最大数据来源，具有丰富的遗传和表型数据 其中包括电子病历，很快将包括30多种生物标志物测定。这使得 检测较小的效果大小，并提供了同时分析多个特征的机会 特别搜索与APOE2的基因环境和基因基因相互作用。我们能够研究 环境因素和生物标志物在APOE2与年龄相关表型之间的关系中的作用 并进行全基因组基因 - 基因相互作用研究，以鉴定APOE2相互作用的变体。这些变体 将使用位置和功能信息（包括EQTL数据）映射到基因 鉴定出的变体的组织特异性表达谱。随后，基于基因和途径（基因 - 设置）将进行分析以获得生物学见解。我们的团队拥有统计遗传学专业， 遗传流行病学，生物信息学，遗传学和临床老年病，包括该领域的领导者 经验衰老队列中的主要基因组分析。拟议的工作是基于我们最近对 UKB的父母寿命，该长寿在与Apoe的先前证明的关联中增加了24种新变体 状态。1该项目的长期目标是澄清与健康成果的正面和负面关联 并了解APOE2和与年龄相关的表型之间的关系。通过整合结果 在与年龄相关的表型中，我们期望阐明APOE2的正相关和负相关 通过潜在的干预措施实现目标的途径，以最终促进健康的衰老。