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

载脂蛋白2与减少阿尔茨海默病的发病率和延长寿命有关。然而， 可能对肾脏疾病和黄斑变性有不良影响的报道也有报道。我们假设 APOE2与年龄相关表型的关系受身体和行为的影响 因子、生化标记物(生物标记物)和遗传变异。到目前为止，老龄化是大多数 慢性病。到目前为止，我们已经发现了许多衰老的生物学途径，这些途径似乎与 慢性病。靶向从载脂蛋白E到衰老和慢性病的途径，效果一致 可能导致总体上非常有利的临床结果。在这个项目中，我们的目标是使用现有的500,000英国 生物库(UKB)参与者识别载脂蛋白2相关表型并表征载脂蛋白E的作用 变种及其相互作用。UKB样本包括21.7万名年龄在60岁至73岁之间的基线受试者，其中10人 多年的临床记录随访。将对已确定的关联进行调查，以了解潜在的 使用物理和行为因素的机制，与APOE2相互作用的遗传相关的途径 变异体和生物标记物是心血管疾病、癌症、肾功能的既定危险因素 和其他结果。UKB数据是同类数据中最大的数据源，具有丰富的遗传和表型数据 这包括电子病历，不久将包括30多种生物标记物分析。这赋予了 检测到较小的效应大小，并提供同时分析多个性状的机会，在 与APOE2的基因-环境和基因-基因相互作用的具体搜索。我们能够研究 环境因素和生物标志物在载脂蛋白2与年龄相关表型关系中的作用 并进行全基因组基因-基因相互作用研究，以确定APOE2相互作用的变体。这些变种 将使用位置和功能信息，包括eQTL数据，将其映射到基因以进行研究 识别的变异体的组织特异性表达谱。其次，基于基因和途径(基因- SET)将进行分析，以获得生物学见解。我们的团队在统计遗传学方面有专长， 遗传流行病学、生物信息学、遗传学和临床老年病学，包括该领域的领导者 在老龄化人群中拥有领先的基因组分析经验。建议的工作建立在我们最近对 UKB中的双亲长寿，在之前证实的与载脂蛋白E相关的基础上增加了24个新的变体 本项目的长期目标是澄清与健康结果的积极和消极联系 并了解载脂蛋白2与年龄相关表型的关系。通过整合结果 通过与年龄相关的表型，我们希望澄清APOE2的正相关和负相关，并确定 以潜在干预措施为目标的途径，最终促进健康老龄化。

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.