ApoE2 and protective molecular signatures in Alzheimer's disease and aging

ApoE2 和阿尔茨海默病和衰老中的保护性分子特征

• 批准号: 10425329
• 负责人: ALEXANDER M KULMINSKI
• 金额: $ 76.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425329
• 关键词: 19q13; Address; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Autopsy; Bioinformatics; Biological; Biology; Birth; Body mass index; Characteristics; Cholesterol; Complex; Data; Education; Environmental Exposure; Genes; Genetic; Genetic Transcription; Genotype; Haplotypes; Heterogeneity; High Density Lipoproteins; Human; Hypertension; Individual; Life; Linkage Disequilibrium; Lipids; Longevity; Low-Density Lipoproteins; Mediation; Molecular Analysis; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Pilot Projects; Predisposition; Proxy; Quantitative Trait Loci; Research; Risk Factors; Role; Sampling; Statistical Methods; Structure; Tissues; Triglycerides; Variant; Work; apolipoprotein E-4; cardiovascular disorder risk; cognitive performance; cohort; density; exome; genetic epidemiology; genetic linkage analysis; improved; indexing; innovation; insight; lipoprotein cholesterol; novel strategies; personalized therapeutic; pleiotropism; protective allele; protective effect; reproductive; sex; statistics; trait; whole genome

Previous research emphasizes pleiotropic effects of the APOE 19q13.3 region variants supporting protective (notably, the APOE e2 allele) and detrimental (the APOE e4 allele) roles in Alzheimer’s disease (AD) and aging. Despite nearly two-decade progress in the APOE research, however, even pathogenic role of the strongest risk factor for AD, the APOE e4 allele, remains poorly understood. Understanding protective role of the e2 allele is lagged behind the APOE e4 research due to, in part, seemingly smaller effects of this allele on AD. This paradoxical situation of a potentially strong role of the APOE locus in AD and aging, and a hampered progress in the ApoE2-Aging-AD research requires new approaches. Our approach is built on core principles of evolutionary biology in genetics of aging- related traits characteristic for post-reproductive life, insights from genetic epidemiology of such traits, and the results of our large-scale pilot study of five human cohorts proving its significance and feasibility. The core of our approach is the association of AD with complex molecular signatures in the APOE region, rather than with a single allele, which include the e2 allele. These signatures are defined by significant differences in linkage disequilibrium (LD) patterns between affected and unaffected subjects. The principal difference between our approach and previous studies of LD structures in the APOE region, making it highly innovative, is that following the core biological principles in genetics of aging- related traits, the effects in the ApoE2-Aging-AD framework are considered to be associated with AD- specific molecular signatures, rather than with those driven by common evolutionarily forces. This difference justifies the focus on extended signatures comprised of the APOE e2 allele and SNPs spread through the entire genome and interacting with this allele. Analysis of molecular signatures provides invaluable opportunity to dissect heterogeneity in action of the APOE e2 allele by identifying personalized (i.e., more homogeneous, group specific) polygenic profiles with stronger protective effect of this allele. The objective of this proposal is to identify personalized polygenic profiles, comprised of the e2 allele, other SNPs in the APOE region, and SNPs spread through the entire genome, with stronger protection in the ApoE2-Aging-AD framework, and identify the role of AD risk factors in these profiles. Specific aims: Aim 1. Identify molecular signatures of AD and life span as a proxy for aging. Aim 2. Dissect heterogeneity and identify commonalities in the molecular signatures. Aim 3. Identify personalized polygenic profiles of AD and aging traits. Aim 4. Use bioinformatics analysis to characterize functional consequences of SNPs and genes.

先前的研究强调APOE 19Q13.3区域变体的多效效应支持 保护性（尤其是ApoE E2等位基因）和有害（ApoE E4等位基因）在阿尔茨海默氏症中的角色 疾病（AD）和衰老。尽管在APOE研究中几乎要取得了几乎十年的进展 APOE E4等位基因AD的强风险因素的致病作用仍然很少理解。 了解E2等位基因的受保护作用落后于APOE E4研究，部分原因是 该等位基因对AD的影响似乎较小。这种矛盾的情况，可能是 广告和衰老中的APOE基因座，以及APOE2 AD AD研究中的阻碍进展需要 新方法。我们的方法基于衰老遗传学进化生物学的核心原理 - 相关特征的特征是后期生命的特征，这些特征的遗传流行病学的见解， 以及我们对五个人类人群的大规模试点研究的结果证明了其意义和可行性。 我们方法的核心是AD与APOE中复杂的分子特征的关联 区域，而不是与单个等位基因，其中包括E2等位基因。这些签名由 影响受试者和未受影响的受试者之间的连锁dissequilibrium（LD）模式的显着差异。 我们的方法与先前对APOE中LD结构的研究之间的主要区别 该地区使其具有很高的创新性，是遵循衰老遗传学的核心生物学原理 - 相关特征，ApoE2 aad框架中的影响被认为与AD相关 特定的分子特征，而不是由共同进化力驱动的特异性特征。这 差异证明对APOE E2等位基因和SNP的扩展签名的重点是合理的 通过整个基因组并与该等位基因相互作用。分子特征的分析提供 通过识别APOE E2的行动中剖析异质性的宝贵机会 个性化（即更均匀，特定组的）多基因剖面具有更强的保护作用 这个等位基因。该建议的目的是确定个性化的多基因概况，包括 E2等位基因，APOE地区的其他SNP，SNP在整个基因组中传播，并带有 在APOE2 AD-AD框架中更强的保护，并确定AD风险因素的作用 概况。具体目的：目标1。确定AD和寿命的分子特征作为衰老的代理。 目标2。解剖异质性并确定分子特征中的共同点。目标3。确定 广告和衰老特征的个性化多基因概况。目标4。使用生物信息学分析 表征SNP和基因的功能后果。