Identifying potentially modifiable exposures to improve telomere health and disease outcomes

项目摘要/摘要 端粒是位于染色体末端的非编码序列，它随着细胞的每次分裂而缩短。 年龄。端粒长度(TL)可能是一个全球性的健康生物标志物，因为较短的端粒长度与 存活率低，与年龄相关的疾病/状况，以及一些癌症。遗传和非遗传因素 影响端粒长度及其潜在机制尚不清楚。我们建议使用英国生物库 描述直接影响或适中端粒长度的可修改暴露的数据，以及如何 人际关系影响健康和疾病风险(对PA-19-073做出反应)。英国生物库提供 特别大的样本量(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维数据，涵盖了早期生活、社会- 经济因素、环境暴露、心理创伤事件，以及生活方式和行为 因素，包括体力活动的加速度计测量。我们假设，识别和识别 与端粒长度相关的行为和环境因素的特征，特别是在老年人 将通过个人化的、非药理学的、以治疗为靶点的端粒的未来努力 干预措施。我们还假设，对基因-环境相互作用的更好理解将支持 使用端粒长度测量来监测个人的健康状况，以提醒卫生保健提供者注意 需要预防性和早期保健，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两者之间的关系中所起的中间作用。 暴露和疾病后果。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，以调查双向暴露和TL原因 两性关系。由于遗传的遗传变异在生命过程中是不变的，它们可以用来进行假冒 随机试验，以产生与混淆和反向因果关系更有力的联系。我们的团队是 多学科，具有统计遗传学、遗传流行病学、生物信息学、临床老年病学、 和体力活动流行病学。该团队已经使用英国生物库制作了几个领先的成果 数据，包括一项关于端粒长度和衰老相关结果的研究，通过与 端粒长度。我们要求提供资金来扩展这项工作，以确定影响 端粒长度，并建立从可调节暴露到端粒长度然后与健康相关的路径 结果。我们的发现将有助于确定个性化干预的可修改暴露的优先顺序 改善端粒健康和疾病结局的最终目标。在未来，我们将寻求复制我们的 关键发现，如果可能，使用美国健康和退休研究样本并设置费用 联盟合作(指控：基因组流行病学中心脏和衰老研究的队列)。

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).