Age, Gene/Environment Susceptibility Study

年龄、基因/环境易感性研究

• 批准号: 7592100
• 负责人: Tamara B. Harris
• 金额: $ 62.06万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592100
• 关键词: Address; Adipocytes; Affect; Age; Alzheimer' s Disease; Ankle; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Area; Atherosclerosis; Behavioral Genetics; Biological Preservation; Blood Pressure; Blood Vessels; Body Composition; Bone Density; Candidate Disease Gene; Cardiovascular system; Cells; Cholesterol; Chondrocytes; Chronic; Classification; Cognition; Complex; Condition; Coronary heart disease; Data; Dementia; Deposition; Diabetes Mellitus; Diagnosis; Disease; Elderly; Emerging Technologies; End Point; Enrollment; Environment; Environmental Risk Factor; Fasting; Fatty acid glycerol esters; Fracture; Gene Mutation; Genealogy; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glucose; Health; Hearing; Hip Osteoarthritis; Hip region structure; Human Genome; Hyperglycemia; Iceland; Infiltration; Inflammation; Insulin; Interleukin-1; Interleukin-4; Interleukin-6; Investigation; Knowledge; Life; Link; Malignant Neoplasms; Measures; Mediating; Medical; Mental Depression; Metabolic Diseases; Methods; Muscle; Muscle Cells; Muscle Development; Musculoskeletal Diseases; Neurocognitive; Northern Europe; Obesity; Osteocytes; Osteoporosis; Outcome; Participant; Patient Self-Report; Peripheral arterial disease; Phenotype; Physical activity; Population; Predisposition; Process; Proteomics; Questionnaires; Rate; Recording of previous events; Research; Risk Factors; Sedimentation process; Smoking; Stem cells; Stream; Stroke; Susceptibility Gene; Testing; Tumor Necrosis Factor-alpha; Upper arm; Vascular Dementia; Ventricular; Vertebral column; Visceral; Vision; Woman; aging gene; apolipoprotein E-4; base; bone; cardiovascular risk factor; coronary artery calcification; cytokine; design; disability; disease phenotype; early onset; follow-up; gene environment interaction; genetic epidemiology; human TNF protein; innovation; men; middle age; mortality; novel; prevent; sarcopenia; trait

The sequencing of the human genome and identification of candidate genes will allow substantial innovation in the study of the contribution of genetics to diseases of old age, especially in conjunction with emerging technologies to understand the corresponding proteomics. Understanding genetic and environmental contributions and their interactions could create novel opportunities to prevent disease and limit disability. The Age, Gene/Environment Susceptibility (AGES) Study was initiated to examine genetic susceptibility and gene/environment interaction as these contribute to phenotypes common in old age. The study has four major focus areas: neurocognitive conditions (cognition, dementia, depression, neurosensory vision and hearing), cardiovascular health (atherosclerosis, arterial distensibility, ventricular and valvular disease), musculoskeletal conditions (spine and hip osteoporosis, hip osteoarthritis, strength and function), and body composition and metabolic disease (obesity, sarcopenia, hyperglycemia/diabetes).Baseline enrollment of 5674 men and women is completed and a follow-up exam is underway. The study is conceived of as a 3-part study. The major aspect of the study is a cross-sectional examination of Reykjavik Study participants to define phenotypes for candidate gene studies. However, these phenotypes will also be used as end-points to be examined in relation to the earlier risk factors collected as part of the Reykjavik Study. This will allow enhanced understanding of factors contributing to disease in old age, apart from genetic factors. Lastly, these phenotypes can be examined in relation to selected outcomes cause-specific mortality, coronary heart disease, fractures, and cancers. With the exception of the apolipoprotein E gene, the importance of genetic contributions to chronic conditions of old age is unclear. Single gene mutations have been associated with early-onset forms of these chronic conditions. Later life disease is hypothesized to reflect multiple genes with small contributions and it has proven difficult to identify these genes using conventional methods that were useful for identification of the early-onset single gene mutations. The AGES Study has been designed to address many of the limitations of genetic epidemiology studies of late-life disease. These include sufficient power, the relatively genetically homogeneous Icelandic population along with the available information about familial relationships from genealogies. Most important is the emphasis on quantitative traits rather than either self-reported conditions or medical diagnosis. The focus areas for the AGES Study also share etiologic hypotheses regarding risk factors, therefore allowing complementary genetic studies of polymorphisms as these might pertain to multiple health conditions. For instance, atherosclerosis, osteoporosis, obesity and glucose abnormalities, Alzheimers Disease and vascular dementia, share hypotheses related to inflammation. We have identified this as one of the areas for genetic investigation in the AGES Study and pla to examine whether polymorphisms in the genes for proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, interleukin-1, or genetic variation in the anti-inflammatory cytokines, interleukin-4, will be associated with phenotypes of these diseases. Another such area involves cells derived from mesechymal stem cells including osteocytes, chondrocytes, myocytes, adipocytes and stroma. As subjects age and change physical activity, there appears to be deposition of fat within muscle and within bone, linked to sarcopenia and to osteoporosis. These processes may be regulated by PPAR-c; genotyping for one condition will allow efficient investigations of potentially related conditions. Several specific research hypotheses include: Alzheimers disease is associated with vascular damage that results from mid-life risk factors such as blood pressure, cholesterol, fasting and post-challenge glucose, and insulin. These risk factors will also be associated with MRI-determined vascular changes, aside from stroke, and will be mediated by markers of inflammation. Genetic susceptibility to vascular changes will contribute to the associations between cardiovascular risk factors and AD. Subclinical late-life atherosclerosis (measured by carotid thickening, aortic and coronary calcification, and low ankle-arm blood pressure ratio, indicative of peripheral arterial disease) reflects the effect of risk factors from midlife such as blood pressure, smoking, cholesterol, fasting and post-challenge glucose, and sedimentation rate. These will interact with candidate genes such as apolipoprotein e4. Lifelong participation in physical activity (measured from earlier and current questionnaires) will be associated with preservation of muscle mass in old age, less fatty infiltration of muscle, lower visceral fat, and higher bone mineral density in both the spine and hip. This will interact with polymorphisms in candidate genes such as the ACE polymorphism that are hypothesized to affect muscle development. There will be a strong relationship between clinically recognized and subclinical CVD and low bone mineral density in the spine and the hip. This relationship will be modified by genetic factors related to inflammation, particularly polymorphisms of the IL-6 and TNF-alpha genes. Although located in Iceland, Icelanders and many U.S. citizens share a common genetic heritage from Northern Europe. It is hoped that the results of this study, besides contributing to knowledge of genetic factors influencing diseases of old age, may also be generalize to the U.S. population.

人类基因组的测序和候选基因的鉴定将允许在研究遗传学对老年疾病的贡献时进行实质性创新，尤其是与新兴技术结合在一起，以了解相应的蛋白质组学。 了解遗传和环境贡献及其相互作用可能会创造新的机会来预防疾病和限制残疾。 开始了年龄，基因/环境易感性（年龄）研究，以检查遗传易感性和基因/环境相互作用，因为这些研究有助于老年常见的表型。 The study has four major focus areas: neurocognitive conditions (cognition, dementia, depression, neurosensory vision and hearing), cardiovascular health (atherosclerosis, arterial distensibility, ventricular and valvular disease), musculoskeletal conditions (spine and hip osteoporosis, hip osteoarthritis, strength and function), and body composition and metabolic disease (obesity,肌肉减少症，高血糖/糖尿病）。5674名男性和女性的基线入学率正在完成，并正在进行后续检查。 该研究被认为是一项三部分研究。 该研究的主要方面是对Reykjavik研究参与者的横断面检查，以定义候选基因研究的表型。 但是，这些表型也将用作终点，以与雷克雅未克研究的一部分收集的早期风险因素有关。 除了遗传因素外，这将使人们对导致疾病的因素的了解增强。 最后，可以根据选定的结果引起特定的死亡率，冠心病，骨折和癌症来检查这些表型。 除载脂蛋白E基因外，遗传贡献对老年慢性条件的重要性尚不清楚。 单基因突变与这些慢性疾病的早期形式有关。 假设以后的生命疾病反映了具有较小贡献的多个基因，事实证明，使用常规方法鉴定这些基因，这些方法对于鉴定早期发作的单基因突变有用。 AGES研究旨在解决晚年疾病的遗传流行病学研究的许多局限性。 这些包括足够的力量，相对遗传上均匀的冰岛人口以及有关家谱中的家族关系的可用信息。 最重要的是强调定量性状，而不是自我报告的疾病或医学诊断。 AGES研究的焦点领域还共享有关危险因素的病因学假设，因此允许对多态性的互补遗传研究，因为这些研究可能与多种健康状况有关。 例如，动脉粥样硬化，骨质疏松症，肥胖和葡萄糖异常，阿尔茨海默氏病和血管性痴呆症具有与炎症有关的假设。 我们已经将其确定为AGES研究和PLA的遗传研究领域之一，可以检查促炎细胞因子基因中的多态性，例如肿瘤坏死因子 - α，介体6，白介素-6，肠介菌-1或遗传变异，抗炎细胞因子中的遗传变异是否与这些禁用属于这些禁用属于这些禁用。 另一个这样的区域涉及源自中学干细胞的细胞，包括骨细胞，软骨细胞，肌细胞，脂肪细胞和基质。 随着受试者的年龄和变化的体育活动，肌肉内和骨骼内似乎存在脂肪沉积，与肌肉减少症和骨质疏松症有关。 这些过程可以由PPAR-C调节；一种条件的基因分型将允许对潜在相关条件的有效研究。 一些特定的研究假设包括： 阿尔茨海默氏病与血管损伤有关，该血管损伤是由中期危险因素（例如血压，胆固醇，禁食和挑战后葡萄糖和胰岛素）引起的。 除了中风，这些危险因素还将与MRI确定的血管变化有关，并将由炎症标记介导。对血管变化的遗传敏感性将导致心血管危险因素与AD之间的关联。 亚临床晚期动脉粥样硬化（通过颈动脉增厚，主动脉钙化和冠状动脉钙化和低脚踝臂血压比测量，表明外周动脉疾病的表明）反映了中年因素的影响，例如血压，吸烟，吸烟，胆固醇，胆固醇，胆固醇，胆固醇，胆固醇和促进性glucose glucose glucose速率和沉积速率。 这些将与候选基因（例如载脂蛋白E4）相互作用。 终身参与体育活动（根据早期和当前的问卷来衡量）将与老年肌肉质量保存有关，肌肉的脂肪浸润较小，内脏脂肪较低以及脊柱和臀部的骨矿物质密度较高。这将与候选基因中的多态性相互作用，例如王牌多态性，这些多态性被认为会影响肌肉发育。 脊柱和臀部的临床认可和亚临床CVD与低骨矿物质密度之间的关系将有很强的关系。 这种关系将通过与炎症有关的遗传因素来改变，尤其是IL-6和TNF-Alpha基因的多态性。 尽管位于冰岛，但冰岛人和许多美国公民拥有来自北欧的共同遗传遗产。 希望这项研究的结果除了有助于影响老年疾病的遗传因素知识之外，还可能推广到美国人群。