The Epidemiology and Somatic Genomic Pathogenesis of Radon-Related Stroke

氡相关中风的流行病学和体细胞基因组发病机制

• 批准号: 10580385
• 负责人: Eric A. Whitsel
• 金额: $ 199.53万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580385
• 关键词: Accounting; Address; Age; American Cancer Society; Atherosclerosis Risk in Communities; Blood Pressure; Carcinogens; Carotid Atherosclerotic Disease; Cerebrovascular Disorders; Characteristics; Classification; Clinical; Cohort Studies; Data Set; Diet; Disease; Environment; Environmental Epidemiology; Environmental Risk Factor; Epidemiology; Event; Foundations; Gases; Genomics; Geology; Goals; Health; Health Policy; Hematopoiesis; Hispanic Community Health Study; Hispanic Community Health Study/Study of Latinos; Home; Housing; Incidence; Koreans; Link; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediation; Mediator; Medicare; Meta-Analysis; Modeling; National Health and Nutrition Examination Survey; National Heart, Lung, and Blood Institute; Occupational; Outcome; Participant; Pathogenesis; Pathologic; Patient Self-Report; Physical activity; Physicians; Play; Policies; Population; Population Heterogeneity; Positioning Attribute; Predisposition; Prevention; Public Health; Race; Radioactive Elements; Radioactivity; Radon; Resolution; Risk Factors; Role; Science; Selection Bias; Smoking; Soil; Special Population; Stroke; Stroke prevention; Testing; Time; Uncertainty; Uranium; Validation; Variant; Women' s Health; adjudication; beneficiary; cerebrovascular; cerebrovascular health; cohort; cryptogenic stroke; design; disability; endothelial dysfunction; genome sequencing; improved; lung carcinogenesis; modifiable risk; mortality; novel; precision medicine; programs; public health intervention; screening; spatiotemporal; statistics; stroke outcome; stroke risk; whole genome

Project Summary/Abstract Although stroke is a major contributor to disability and mortality worldwide, established stroke risk factors have not fully explained the observed burden of or spatial variation in its incidence. Indeed, nearly a third of strokes are cryptogenic, thereby compelling a search for environmental factors that may play an important, but to date, inadequately characterized role in stroke pathogenesis and epidemiology. One such factor—radon—is a naturally occurring, odorless gas generated via decay of radioactive elements in rocks and soils. The gas enters homes through basement and foundation cracks, making unrecognized exposures both ubiquitous and the second-leading, modifiable cause of lung cancer in the US, after smoking. Although radon’s role in lung carcinogenesis is well-known, relatively little is known about its role in the pathogenesis and epidemiology of cerebrovascular disease. Yet extant studies of the radon-stroke association suggest that radon exposure is associated both with pathologic precursors of stroke and incident stroke, itself. Their collective limitations nonetheless leave a substantial gap in the state of the science that could otherwise highlight putative means of reducing radon exposures and their common cerebrovascular sequelae in the US. To fill this gap, we will therefore estimate: [1] pre- and post-mitigation home radon exposures across the US (1986-2018), [2] the association between time-varying home radon exposure and incident stroke, [3] the association between time- varying home radon exposure and clonal hematopoiesis of indeterminate potential (CHIP), and [4] mediation of the radon-stroke association by CHIP. We will do so among a demographically and environmentally diverse group of 194,015 participants in three NHLBI-supported cohorts that have reviewed and approved this proposal. Quantitatively estimating radon exposures and their uncertainties at their accurately geocoded addresses will involve a national, spatiotemporal prediction and two-stage cross-validation based on time-varying, short- and long-term mean, pre- and post-mitigation home radon concentrations; home radon testing statistics / policies; and housing characteristics; plus, time-invariant aerial gamma-radioactivity, geology, and soil features. Estimating radon-stroke and radon-CHIP associations also will involve cohort-specific, multivariable-adjusted, Bayesian, hierarchical, time-to-event and logistic regression accounting for exposure uncertainty and competing mortality, followed by inverse variance-weighted, random-effects meta-analysis. Finally, estimating mediation of the radon-stroke association by CHIP will involve quantifying direct, indirect, and total effects of radon on stroke. The previously unparalleled focus of such estimation on a modifiable risk factor, a plausible mechanism of disease, and a common, clinically and societally burdensome health outcome heretofore ignored by EPA and WHO uniform radon testing and mitigation policies will thereby position the study to help characterize the environmental epidemiology and somatic genomic pathogenesis of stroke and other health outcomes in ways that may lead to the identification of plausible targets for new public health screening and prevention efforts.

项目概要/摘要 尽管中风是全世界残疾和死亡的主要原因，但已确定的中风危险因素 没有完全解释观察到的中风负担或发病率的空间变化。事实上，近三分之一的中风。 是隐源性的，因此迫使人们寻找可能发挥重要作用的环境因素，但迄今为止， 其中一个因素——氡气——是 岩石和土壤中放射性元素衰变产生的自然产生的无味气体。 房屋通过地下室和地基裂缝，使得未被识别的暴露无处不在， 尽管氡气在肺癌中的作用，但它是美国肺癌的第二大、可改变的原因，仅次于吸烟。 致癌作用是众所周知的，但对其在发病机制和流行病学中的作用知之甚少。 然而，现有的氡气与中风关联的研究表明，氡气暴露与脑血管疾病有关。 与中风的病理前兆和突发中风本身有关。 然而，在科学状况上留下了巨大的空白，否则可能会凸显假定的手段 减少美国的氡暴露及其常见的脑血管后遗症 为了填补这一空白，我们将 因此估计：[1] 美国各地缓解前和缓解后的家庭氡气暴露量（1986-2018 年），[2] 随时间变化的家庭氡气暴露与中风事件之间的关联，[3] 时间- 不同的家庭氡暴露和不确定潜力的克隆造血（CHIP），以及[4]的介导 CHIP 的氡气中风协会 我们将在人口和环境多样化的人群中这样做。 由 NHLBI 支持的三个队列中的 194,015 名参与者组成的小组已审查并批准了该提案。 定量估计准确地理编码地址处的氡气暴露及其不确定性 涉及全国时空预测和基于时变、短时和时变的两阶段交叉验证 长期平均、缓解前和缓解后的家庭氡气浓度测试统计/政策； 和住房特征；加上时不变的空中伽马放射性、地质和土壤特征。 估计氡气-中风和氡气-CHIP 关联还将涉及特定队列、多变量调整、 贝叶斯、分层、事件时间和逻辑回归解释了暴露不确定性和竞争 死亡率，然后进行逆方差加权、随机效应荟萃分析，最后估计中介作用。 CHIP 的氡气与中风关联将涉及量化氡气对中风的直接、间接和总体影响。 这种估计前所未有地关注可改变的风险因素，这是一种合理的机制 疾病，以及一种常见的、临床和社会负担的健康结果，迄今为止被 EPA 和 因此，世卫组织统一的氡气测试和缓解政策将使该研究有助于描述氡气的特征。 中风和其他健康结果的环境流行病学和体细胞基因组发病机制 这可能会导致确定新的公共卫生筛查和预防工作的合理目标。