Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States. METHODS: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics. RESULTS: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L (p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses. DISCUSSION: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.

Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Studies suggest that clonal hematopoiesis of indeterminate potential (CHIP) may increase risk of hematologic malignancy and cardiovascular disease, including stroke. However, few studies have investigated plausible environmental risk factors for CHIP such as radon, despite the climate-related increases in and documented infrequency of testing for this common indoor air pollutant.The purpose of this study was to estimate the risk of CHIP related to radon, an established environmental mutagen. METHODS: We linked geocoded addresses of 10,799 Women's Health Initiative Trans-Omics for Precision Medicine (WHI TOPMed) participants to US Environmental Protection Agency-predicted, county-level, indoor average screening radon concentrations, categorized as follows: Zone 1 (>4 pCi/L), Zone 2 (2-4 pCi/L), and Zone 3 (<2 pCi/L). We defined CHIP as the presence of one or more leukemogenic driver mutations with variant allele frequency >0.02. We identified prevalent and incident ischemic and hemorrhagic strokes; subtyped ischemic stroke using Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria; and then estimated radon-related risk of CHIP as an odds ratio (OR) and 95% CI using multivariable-adjusted, design-weighted logistic regression stratified by age, race/ethnicity, smoking status, and stroke type/subtype. RESULTS: The percentages of participants with CHIP in Zones 1, 2, and 3 were 9.0%, 8.4%, and 7.7%, respectively (ptrend = 0.06). Among participants with ischemic stroke, Zones 2 and 1 were associated with higher estimated risks of CHIP relative to Zone 3: 1.39 (1.15-1.68) and 1.46 (1.15-1.87), but not among participants with hemorrhagic stroke: 0.98 (0.68-1.40) and 1.03 (0.70-1.52), or without stroke: 1.04 (0.74-1.46) and 0.95 (0.63-1.42), respectively (pinteraction = 0.03). Corresponding estimates were particularly high among TOAST-subtyped cardioembolism: 1.78 (1.30-2.47) and 1.88 (1.31-2.72), or other ischemic etiologies: 1.37 (1.06-1.78) and 1.50 (1.11-2.04), but not small vessel occlusion: 1.05 (0.74-1.49) and 1.00 (0.68-1.47), respectively (pinteraction = 0.10). Observed patterns of association among strata were insensitive to attrition weighting, ancestry adjustment, prevalent stroke exclusion, separate analysis of DNMT3A driver mutations, and substitution with 3 alternative estimates of radon exposure. DISCUSSION: The robust elevation of radon-related risk of CHIP among postmenopausal women who develop incident cardioembolic stroke is consistent with a potential role of somatic genomic mutation in this societally burdensome form of cerebrovascular disease, although the mechanism has yet to be confirmed.

Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in white blood cells, has been associated with increased risk of atherosclerotic cardiovascular diseases, cancer, and mortality. OBJECTIVE: We examined the relationship between individual- and neighborhood-level socioeconomic status (SES) and CHIP and evaluated effect modification by interpersonal and intrapersonal resources. METHODS: The study population included 10,799 postmenopausal women from the Women's Health Initiative without hematologic malignancy or antineoplastic medication use. Individual- and neighborhood (Census tract)-level SES were assessed across several domains including education, income, and occupation, and a neighborhood-level SES summary z-score, which captures multiple dimensions of SES, was generated. Interpersonal and intrapersonal resources were self-reports. CHIP was ascertained based on a prespecified list of leukemogenic driver mutations. Weighted logistic regression models adjusted for covariates were used to estimate risk of CHIP as an odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The interval-scale neighborhood-level SES summary z-score was associated with a 3% increased risk of CHIP: OR (95% CI) = 1.03 (1.00-1.05), p = .038. Optimism significantly modified that estimate, such that among women with low/medium and high levels of optimism, the corresponding ORs (95% CIs) were 1.03 (1.02-1.04) and 0.95 (0.94-0.96), pInteraction < .001. CONCLUSIONS: Our findings suggest that reduced risk of somatic mutation may represent a biological pathway by which optimism protects contextually advantaged but at-risk women against age-related chronic disease and highlight potential benefits of long-term, positive psychological interventions.