From the Department of Epidemiology (K.M.A., J.M.C., S.-A.M.L., J.D.S., R.G., E.A.W.), Gillings School of Global Public Health, University of North Carolina, Chapel Hill; Brown University (S.F.B.), Providence, RI; Department of Population Health (G.G.S.), University of North Dakota School of Medicine & Health Sciences, Grand Forks; Department of Neurology (D.Y.H.), School of Medicine, University of North Carolina, Chapel Hill; Program in Public Health (J.R.M.), Stony Brook University, Stony Brook, NY; Division of Oncological Sciences (Z.Z.), Knight Cancer Institute, Oregon Health & Science University, Portland; Department of Cardiology (A.B.), Medstar Washington Hospital Center, Washington, DC; Department of Medicine (A.B.), Georgetown University, Washington, DC; Division of Hematology and Oncology (P.D.), Weill Cornell Medicine, New York; Department of Social Sciences and Health Policy (K.M.H.), Wake Forest University School of Medicine, Winston-Salem, NC; Cardiology Division (M.C.H.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (M.C.H., P.N.), Broad Institute of Harvard and MIT, Cambridge, MA; Department of Pathology (S.J.), Stanford University School of Medicine, CA; Cardiovascular Research Center and Center for Genomic Medicine (P.N.), Massachusetts General Hospital, Boston; Department of Medicine (P.N.), Harvard Medical School, Boston; Division of Genetic Medicine (A.G.B.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Division of Public Health Sciences (C.K., A.P.R.), Fred Hutchinson Cancer Center, Seattle, WA; Department of Medicine (J.E.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Epidemiology (A.P.R.), University of Washington, Seattle; and Department of Medicine (E.A.W.), School of Medicine, University of North Carolina, Chapel Hill.
Neurology. 2024 Jan 23;102(2):e208055. doi: 10.1212/WNL.0000000000208055. Epub 2024 Jan 3.
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.
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.
The percentages of participants with CHIP in Zones 1, 2, and 3 were 9.0%, 8.4%, and 7.7%, respectively ( = 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 ( = 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 ( = 0.10). Observed patterns of association among strata were insensitive to attrition weighting, ancestry adjustment, prevalent stroke exclusion, separate analysis of driver mutations, and substitution with 3 alternative estimates of radon exposure.
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.
研究表明，不确定潜能的克隆性造血（CHIP）可能会增加血液系统恶性肿瘤和心血管疾病（包括中风）的风险。然而，尽管气候相关因素增加了这种常见室内空气污染物的检测频率，但很少有研究调查 CHIP 的潜在环境风险因素，如氡。本研究的目的是评估与已确定的环境诱变剂氡相关的 CHIP 风险。
我们将 10799 名妇女健康倡议跨组学精准医学（WHI TOPMed）参与者的地理位置编码地址与美国环境保护署预测的县一级室内平均筛查氡浓度相关联，分为以下三个区域：区域 1（>4 pCi/L）、区域 2（2-4 pCi/L）和区域 3（<2 pCi/L）。我们将 CHIP 定义为存在一种或多种白血病驱动突变，其变异等位基因频率>0.02。我们确定了缺血性和出血性中风的现患和新发病例；根据临床试验中的组织型纤溶酶原激活剂治疗急性缺血性脑卒中（TOAST）标准对缺血性中风进行亚型分类；然后，使用多变量调整、设计权重逻辑回归，按年龄、种族/民族、吸烟状况和中风类型/亚型分层，估计 CHIP 与氡相关的风险比（OR）和 95%置信区间（CI）。
区域 1、2 和 3 中 CHIP 患者的百分比分别为 9.0%、8.4%和 7.7%（=0.06）。在缺血性中风患者中，与区域 3 相比，区域 2 和区域 1 与更高的 CHIP 估计风险相关：1.39（1.15-1.68）和 1.46（1.15-1.87），但在出血性中风患者中并非如此：0.98（0.68-1.40）和 1.03（0.70-1.52），或在无中风患者中也并非如此：1.04（0.74-1.46）和 0.95（0.63-1.42），差异有统计学意义（=0.03）。在 TOAST 分型的心源性栓塞中，相应的估计值特别高：1.78（1.30-2.47）和 1.88（1.31-2.72），或其他缺血性病因：1.37（1.06-1.78）和 1.50（1.11-2.04），但小血管闭塞时并非如此：1.05（0.74-1.49）和 1.00（0.68-1.47），差异有统计学意义（=0.10）。各分层之间的关联模式观察到的一致性对缺失值加权、祖先调整、排除现患中风、单独分析驱动突变以及用 3 种替代氡暴露估计值进行替代的敏感性较高。
在发生心源性栓塞性中风的绝经后妇女中，氡相关 CHIP 风险显著升高，这与体细胞基因组突变在这种具有社会负担的脑血管疾病中可能发挥作用一致，尽管其机制尚未得到证实。
