Identifying potentially modifiable exposures to improve telomere health and disease outcomes

识别潜在可改变的暴露以改善端粒健康和疾病结果

• 批准号: 10057808
• 负责人: Chia-Ling Kuo
• 金额: $ 24.79万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057808
• 关键词: Accelerometer; Address; Age; Aging; Alcohol consumption; Applications Grants; Behavioral; Bioinformatics; Biological Markers; Buffers; Cell division; Chromosomes; Chronic; Clinical; Collaborations; Collection; Complex; Coronary heart disease; Data; Disease; Disease Outcome; Economic Factors; Environment; Environmental Exposure; Environmental Risk Factor; Environmental and Occupational Exposure; Epidemiology; Etiology; European; Exposure to; Funding; Future; Gene Expression; Genes; Genetic; Geriatrics; Goals; Health; Health Personnel; Health Status; Health and Retirement Study; Healthcare; Heart; Individual; Infectious Agent; Inflammation; Inherited; Intervention; Length; Leukocytes; Life; Life Style; Literature; Malignant Neoplasms; Measurement; Measures; Mediating; Methods; Modeling; Monitor; Observational Study; Outcome; Output; Oxidative Stress; Participant; Physical activity; Preventive; Reporting; Research; Rest; Risk; Role; Sample Size; Sampling Studies; Sleep Deprivation; Smoking; Stress; Telomere Shortening; Testing; Untranslated RNA; Variant; Work; age related; biobank; cancer risk; cohort; disorder risk; gene environment interaction; genetic epidemiology; genetic variant; genome wide association study; genomic epidemiology; improved; multidimensional data; multidisciplinary; non-genetic; novel; perceived stress; personalized intervention; phenotypic data; psychologic; randomized trial; repaired; resilience; socioeconomics; telomere; therapeutic target; trait; traumatic event

Project Summary/Abstract Telomeres are non-coding sequences at the end of chromosomes that shorten with each cell division as we age. Telomere length (TL) may be a global biomarker of health, as shorter telomere length is associated with poor survival, age-related diseases/conditions, and some cancers. Both genetic and non-genetic factors influence telomere length and the underlying mechanisms remain unclear. We propose to use UK Biobank data to delineate modifiable exposures that directly influence or moderate telomere length, and how the relationships influence health and risk of disease (responding to PA-19-073). UK Biobank offers an exceptionally large sample size (over 500,000 participants), with telomere length measures, genetic and phenotypic data. Most notably, it provides multidimensional data on exposures, covering early life, socio- economic factors, environmental exposures, psychologically traumatic events, plus lifestyle and behavioral factors, including accelerometer measures of physical activity. We hypothesize that identifying and characterizing behavioral and environmental factors associated with telomere length, especially in older groups, will inform future efforts to therapeutically target telomeres through personalized, non-pharmacological interventions. We also hypothesize that a better understanding of gene-environment interactions will support the use of telomere length measurement for monitoring individual health status, to alert health providers to the need for preventive and early health care, ultimately improving health outcomes. We aim to conduct an environment-wide association study (EWAS) to identify novel exposures and gene-environment interactions on telomere length. We also will examine the intermediate role of telomere length in the relationships between exposures and disease outcomes. Additionally, we aim to strengthen our EWAS by inherited genetic variants associated with exposures and telomere length, to investigate bidirectional exposure and TL causal relationships. As inherited genetic variants are unchanging during life, they can be used to conduct pseudo randomized trials to produce more robust associations to confounding and reverse causation. Our team is multidisciplinary, with expertise in statistical genetics, genetic epidemiology, bioinformatics, clinical geriatrics, and physical activity epidemiology. The team has already produced several leading outputs using UK Biobank data, including a study on telomere length and aging-related outcomes via genetic variants associated with telomere length. We request funding to extend this work to identify novel modifiable exposures influencing telomere length, and establish the path from modifiable exposures to telomere length and then health-related outcomes. Our findings will be useful to prioritize modifiable exposures for personalized interventions with the ultimate goal of improving telomere health and disease outcomes. In the future, we will seek to replicate our key findings, where possible, using the US Health and Retirement study samples and set up a CHARGE consortium collaboration (CHARGE: Cohorts for Heart and Aging Research in Genomic Epidemiology).

项目总结/摘要 端粒是染色体末端的非编码序列，随着细胞分裂而缩短， 年龄端粒长度（TL）可能是全球健康的生物标志物，因为较短的端粒长度与 存活率低、与年龄有关的疾病/状况和某些癌症。遗传和非遗传因素 影响端粒长度和潜在的机制尚不清楚。我们建议使用英国生物银行 数据来描述直接影响或调节端粒长度的可变暴露，以及 关系影响健康和疾病风险（对PA-19-073的回应）。英国生物银行提供了一个 异常大的样本量（超过500，000名参与者），端粒长度测量，遗传和 表型数据最值得注意的是，它提供了关于暴露的多方面数据，涵盖了早期生活、社会和文化背景。 经济因素，环境暴露，心理创伤事件，加上生活方式和行为 因素，包括身体活动的加速计测量。我们假设， 描述与端粒长度相关的行为和环境因素，特别是在老年人中， 研究小组，将告知未来的努力，通过个性化的，非药理学的治疗目标端粒 干预措施。我们还假设，更好地了解基因-环境相互作用将支持 使用端粒长度测量来监测个人健康状况，以提醒健康提供者注意 需要预防和早期保健，最终改善健康结果。我们的目标是进行一项 全环境关联研究（EWAS），以确定新的暴露和基因-环境相互作用， 端粒长度我们还将研究端粒长度在以下关系中的中间作用： 暴露和疾病结果。此外，我们的目标是通过遗传变异来加强我们的EWAS 与暴露和端粒长度相关，以研究双向暴露和TL因果关系 关系。由于遗传的遗传变异在生命过程中是不变的，它们可以用来进行伪 随机试验，以产生更强大的关联，混淆和反向因果关系。我们的团队是 多学科，在统计遗传学，遗传流行病学，生物信息学，临床老年医学， 和体力活动流行病学。该团队已经使用英国生物库产生了几个领先的输出 数据，包括一项关于端粒长度和衰老相关结果的研究， 端粒长度我们要求提供资金，以扩大这项工作，以确定新的可改变的暴露影响 端粒长度，并建立从可变暴露到端粒长度的路径，然后与健康相关 结果。我们的研究结果将有助于优先考虑可修改的暴露，以进行个性化干预， 改善端粒健康和疾病结果的最终目标。在未来，我们将努力复制我们的 关键发现，在可能的情况下，使用美国健康和退休研究样本，并建立一个收费 CHARGE：Cohorts for Heart and Aging Research in Genomic Epidemiology（心脏和衰老基因组流行病学研究队列）