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: 10170216
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170216
• 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.

先前的研究强调了APOE 19q13.3区域变异的多效性效应， 在阿尔茨海默病中的保护性（特别是APOE e2等位基因）和有害性（APOE e4等位基因）作用 疾病（AD）和衰老。尽管APOE研究取得了近20年的进展，但即使 AD的最强危险因素APOE e4等位基因的致病作用仍然知之甚少。 理解e2等位基因的保护作用落后于APOE e4研究，部分原因是， 这种等位基因对AD的影响似乎较小。这种矛盾的情况下，一个潜在的强大的作用， AD和衰老中的APOE基因座，以及ApoE 2-衰老-AD研究的阻碍进展， 新方法。我们的方法是建立在衰老遗传学进化生物学的核心原则上的- 生殖后生活的相关特征，这些特征的遗传流行病学的见解， 我们对五个人类队列的大规模试点研究结果证明了其重要性和可行性。 我们方法的核心是AD与APOE中复杂分子特征的关联 区域，而不是具有单个等位基因，其包括e2等位基因。这些签名定义如下： 受影响和未受影响的受试者之间的连锁不平衡（LD）模式的显着差异。 我们的方法与以往关于APOE中LD结构的研究之间的主要区别是 区域，使其高度创新，是遵循衰老遗传学的核心生物学原理- 相关性状，认为ApoE 2-衰老-AD框架中的效应与AD相关。 特定的分子特征，而不是那些由共同的进化力量驱动的分子。这 这种差异证明了对由APOE e2等位基因和SNP散布组成的扩展签名的关注是合理的 并与这个等位基因相互作用。分子特征分析提供了 这是一个非常宝贵的机会，可以通过鉴定 个性化（即，更均匀，组特异性）多基因谱，具有更强的保护作用 这个等位基因。该提案的目的是确定个性化的多基因谱，包括 e2等位基因，APOE区域的其他SNP，以及遍布整个基因组的SNP， 在ApoE 2-衰老-AD框架中提供更强的保护，并确定AD风险因素在其中的作用 数据区.具体目标：目标1。识别AD和寿命的分子特征作为衰老的代理。 目标二。剖析异质性并识别分子特征中的共性。目标3。识别 AD和衰老特征的个性化多基因谱。目标4。利用生物信息学分析， 描述SNPs和基因的功能后果。