Genetic Factors that Impact the Risk of Alzheimer's Disease

影响阿尔茨海默病风险的遗传因素

• 批准号: 7813090
• 负责人: ALLEN D ROSES
• 金额: $ 41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813090
• 关键词: Address; Affect; Age; Age of Onset; Aging; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; American; Apolipoprotein E; Applications Grants; Area; Bioinformatics; Case-Control Studies; Characteristics; Clinical; Clinical Research; Code; Complex; Computational Biology; Data; Defect; Dementia; Development; Diagnostic; Disease; Environmental Risk Factor; Funding; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Haplotypes; Impaired cognition; In Vitro; Individual; Institutes; Intervention; Japan; Late Onset Alzheimer Disease; Lead; Length; Link; Linkage Disequilibrium; Literature; Longitudinal Studies; Mediation; Medical; Medicare; Medicine; Methods; Mitochondria; Neurologic; Nucleotides; Odds Ratio; Other Genetics; Outer Mitochondrial Membrane; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phylogenetic Analysis; Population; Population Control; Prevention; Preventive; Probability; Protein Isoforms; Proteins; Public Domains; Randomized; Research Design; Resolution; Risk; Risk Factors; Sample Size; Sampling; Schedule; Science; Signal Transduction; Source; Testing; Universities; Variant; Vertebral column; age related; base; clinically relevant; cost; density; design; disorder risk; drug discovery; effective therapy; evidence base; genetic analysis; genetic variant; high risk; improved; insertion/deletion mutation; meetings; mitochondrial dysfunction; novel; prevent; programs; prospective; protein protein interaction; research study; simulation; tool; translocase; virtual

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08- AG-101: Genetic factors affecting rates of change in disease risk factors with age. Alzheimer's disease (AD) is the most critical unmet need in neurological medicine because there are no disease- modifying therapies that improve the dementia or cognitive decline associated with it. Over 5 million Americans suffer from AD and unless effective therapies for preventing or delaying its onset are developed, it is estimated that more than 16 million Americans will suffer from AD by 2050. The science described in this grant application has the real potential of being transformational to clearly identify specific genetic factors that affect the rate of development of AD and to identify preventive therapies and approaches for healthier aging. The general relationship between APOE genotype and the age of onset for AD is well-documented since 1993. Recent preliminary results show that age of onset of AD is a function of at least two pathogenesis specific genes APOE and TOMM40, each with multiple determinants that affect their protein-protein interactions, residing on the same linkage disequilibrium (LD) region. This proposal develops and tests the paradigm that specific variants are cis- linked to APOE ¿3 and are associated with changes in the age of onset distribution for Alzheimer's disease (AD). The most significant variants of TOMM40 have evolved on the backbone or cis to APOE ¿3 LD region, and not cis to the APOE ¿4 LD region. The TOMM40 gene, which codes for the translocase of the outer mitochondrial membrane, interacts with APOE proteins, modified by the configuration of TOMM40 and the specific APOE isoform. As a consequence of these findings, an AD prevention trial is planned to validate the predictive accuracy of the genetically-based diagnostic and to test a specific preventive drug. Development of disease risk with age may be a function of many small genetic and environmental factors. The proposed approach provides a novel framework for genetic analysis of complex diseases that involve multiple small signals from several interacting genes and is well-aligned with the availability of deep-sequencing data and with phenotypic data available from long-term longitudinal studies available in the public domain. Changes in mitochondrial function are associated with many diseases of aging: by clearly elucidating genetic variants in TOMM40 associated with age-related disease risk, interventions will be identified to delay the onset of AD. Completion of the program will greatly augment the evidence base for the genetic factors that influence the development of AD with age, test approaches for AD prevention and provide powerful bioinformatic tools to study other clinically-relevant diseases in the context of age-related risk. Alzheimer's disease is a critical unmet medical need because there are no disease-modifying therapies that improve the dementia or cognitive decline associated with it. Over 5 million Americans suffer from AD at a cost of $91 billion annually to Medicare alone. Our studies build on a new genetics discovery to understand genetic factors affecting the rate of change in disease risk for AD with age that will lead to the discovery of preventive therapies for Alzheimer's disease.

描述（由申请人提供）： 该应用程序解决了广泛的挑战领域（08）基因组学和特定挑战主题，08- AG-101：影响年龄变化危险因素变化率的遗传因素。阿尔茨海默氏病（AD）是神经医学中最关键的未满足需求，因为没有疾病改善与之相关的痴呆症或认知能力下降的疾病。超过500万美国人患有AD，除非开发出有效的预防或延迟其发作的有效疗法，否则据估计，到2050年，超过1600万美国人将遭受AD的苦难。该赠款应用中所描述的科学具有真正的变革潜力，可以清楚地识别影响AD的发展速度的特定遗传因素，并能够识别出AD的开发率，并确定了预防性疗法和对健康的衰老方法。自1993年以来，APOE基因型与AD发作年龄之间的一般关系已得到充分证明。最近的初步结果表明，AD的发作年龄至少是两个发病机理特异性基因ApoE和Tomm40的函数，每个基因都有多个决定蛋白质相互作用的蛋白质相互作用，这些蛋白质相互作用属于同一链接dissequage Diseperibibiribiribim（LD）区域。该提案发展并测试了特定变体与ApoE€3相关的范式，并与阿尔茨海默氏病（AD）的发作分布年龄变化有关。 Tomm40的最重要变体已在主链或顺式上演变为ApoE„ 3 ld区域，而不是顺式，而不是apoE„ 4 ld区域。 TOMM40基因编码外部线粒体膜的易位酶，与APOE蛋白相互作用，通过Tomm40和特定的APOE同工型的构型进行了修改。由于这些发现，计划进行AD预防试验，以验证基于遗传的诊断的预测准确性并测试特定的预防药物。随着年龄的增长，疾病风险的发展可能是许多小遗传和环境因素的函数。所提出的方法为复杂疾病的遗传分析提供了一个新的框架，该疾病涉及来自几个相互作用基因的多个小信号，并且与深入序列数据的可用性以及可从公共领域中可用的长期纵向研究获得的表型数据相结合。线粒体功能的变化与许多衰老疾病有关：通过清楚阐明与年龄相关疾病风险相关的Tomm40的遗传变异，将确定干预措施以延迟AD的发作。该计划的完成将大大提高影响AD发展的遗传因素的证据基础，预防AD的测试方法，并提供强大的生物信息学工具，以研究与年龄相关的风险背景下其他临床上相关的疾病。阿尔茨海默氏病是一种至关重要的未满足医疗需求，因为没有改善疾病的疗法可以改善与之相关的痴呆症或认知能力下降。超过500万美国人的广告遭受损失，仅在医疗保险上每年为910亿美元。我们的研究以新的遗传学发现为基础，以了解影响AD与年龄变化风险变化率的遗传因素，这将导致发现阿尔茨海默氏病的预防疗法。