Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative
Kurtis M Anthony, Jason M. Collins, Shelly‐Ann Love, James D. Stewart, Sophie F. Buchheit, Rahul Gondalia, Gary G. Schwartz, David Huang, Jaymie R. Meliker, Zhenzhen Zhang, Ana Barac, Pinkal Desai, Kathleen M. Hayden, Michael C. Honigberg, Siddhartha Jaiswal, Pradeep Natarajan, Alexander G. Bick, Charles Kooperberg, JoAnn E. Manson, Alex P. Reiner, Eric A. Whitsel
Abstract
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: 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.