Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Sci Rep. 2022 May 4;12(1):7248. doi: 10.1038/s41598-022-09604-z.
Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) represent two forms of clonal hematopoiesis where clones bearing expanded somatic mutations have been linked to both oncologic and non-oncologic clinical outcomes including atherosclerosis and all-cause mortality. Epidemiologic studies have highlighted smoking as an important driver of somatic mutations across multiple tissues. However, establishing the causal role of smoking in clonal hematopoiesis has been limited by observational study designs, which may suffer from confounding and reverse-causality. We performed two complementary analyses to investigate the role of smoking in mCAs and CHIP. First, using an observational study design among UK Biobank participants, we confirmed strong associations between smoking and mCAs. Second, using two-sample Mendelian randomization, smoking was strongly associated with mCA but not with CHIP. Overall, these results support a causal association between smoking and mCAs and suggest smoking may variably shape the fitness of clones bearing somatic mutations.
克隆性造血的不定潜能（CHIP）和镶嵌性染色体改变（mCAs）代表两种克隆性造血形式，其中携带扩展体细胞突变的克隆与包括动脉粥样硬化和全因死亡率在内的肿瘤和非肿瘤临床结局相关。流行病学研究强调了吸烟是多种组织体细胞突变的重要驱动因素。然而，由于观察性研究设计可能存在混杂和反向因果关系，因此确定吸烟在克隆性造血中的因果作用受到了限制。我们进行了两项互补分析，以调查吸烟在 mCAs 和 CHIP 中的作用。首先，我们在英国生物库参与者中采用观察性研究设计，证实了吸烟与 mCAs 之间存在强烈关联。其次，采用两样本孟德尔随机化，吸烟与 mCA 强烈相关，但与 CHIP 无关。总的来说，这些结果支持吸烟与 mCAs 之间存在因果关系，并表明吸烟可能会改变携带体细胞突变的克隆的适应性。
