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

ApoE 2与阿尔茨海默病的发病率降低和寿命延长有关。然而，在这方面， 还报道了对肾病和黄斑变性的可能的不利影响。我们假设 ApoE 2与年龄相关表型之间的关系受到身体和行为的影响， 因子、生物化学标志物（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风险因素。 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，这些途径似乎是由 慢性病靶向从ApoE到衰老和慢性疾病的途径，具有一致的效果 可能导致总体上非常有利的临床结果。在这个项目中，我们的目标是利用现有的50万英国 生物样本库（UKB）参与者确定ApoE 2相关表型并表征ApoE的作用 变量及其相互作用。UKB样本包括基线时年龄在60至73岁的217，000名受试者，其中10名受试者在基线时年龄在60至73岁之间。 多年的临床记录随访。将调查已确定的关联，以了解潜在的 使用身体和行为因素的机制，与ApoE 2相互作用的遗传相关的途径， 变异和生物标志物是心血管疾病、癌症、肾功能 和其他成果。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 这包括电子医疗记录，并将很快包括超过30个生物标志物测定。这使 检测较小的效应量，并提供了同时分析多个性状的机会， 特别是寻找与ApoE 2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ApoE 2与年龄相关表型关系中的作用 并进行全基因组基因间相互作用研究，以鉴定ApoE 2相互作用变体。这些变体 将使用位置和功能信息定位到基因，包括eQTL数据，以研究 鉴定的变体的组织特异性表达谱。随后，基于基因和途径（基因- 将进行分析以获得生物学见解。我们的团队有统计遗传学方面的专长， 遗传流行病学，生物信息学，遗传学和临床老年病学，并包括该领域的领导者， 在老龄化群体中进行领先的基因组分析。拟议的工作建立在我们最近的分析， UKB的父母寿命，这增加了24个新的变异，以前证明与ApoE的关联 1本项目的长期目标是澄清与健康结果的积极和消极联系 了解ApoE 2与年龄相关表型的关系。通过整合结果 在年龄相关的表型中，我们希望澄清ApoE 2的阳性和阴性相关性，并确定 通过潜在的干预措施，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.