Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Curr Opin Cardiol. 2020 May;35(3):219-225. doi: 10.1097/HCO.0000000000000726.
While advanced age is the major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), we have a poor understanding of how aging promotes the progression of this disease. Recent evidence suggests that the age-dependent accumulation of somatic mutations in hematopoietic cells may represent a new causal risk factor for ASCVD.
A hallmark of aging is the accumulation of somatic DNA mutations in all tissues of the body. Accordingly, evidence shows that hematopoietic stem/progenitor cells accumulate somatic mutations as a function of age in nonsymptomatic individuals. When these mutations occur in driver genes that provide a selective advantage to the hematopoietic stem/progenitor cells, they undergo a clonal expansion and progressively give rise to blood leukocytes that harbor these mutations. This phenomenon, referred to as clonal hematopoiesis, has been associated with the increased risk of mortality, hematologic malignancy, ASCVD, and related diseases. Notably, many individuals exhibiting clonal hematopoiesis carry single 'driver' mutations in preleukemic genes including DNA methyltransferase 3a, ten-eleven translocation 2, additional sex combs like 1, and Janus kinase 2. Experimental studies show that these mutations in some of these genes can alter the inflammatory properties of the leukocyte and contribute to the pathogenesis of ASCVD.
We review recent epidemiological and experimental findings on the association between age-related clonal hematopoiesis and ASCVD by focusing on prevalent driver gene mutations.
虽然高龄是动脉粥样硬化性心血管疾病（ASCVD）发展的主要危险因素，但我们对衰老如何促进这种疾病的进展知之甚少。最近的证据表明，造血细胞中与年龄相关的体细胞突变的积累可能代表 ASCVD 的一个新的因果危险因素。
衰老的一个标志是身体所有组织中体细胞 DNA 突变的积累。因此，有证据表明，在无症状个体中，造血干/祖细胞随年龄的增长积累体细胞突变。当这些突变发生在为造血干/祖细胞提供选择性优势的驱动基因中时，它们会发生克隆扩张，并逐渐产生携带这些突变的血液白细胞。这种现象被称为克隆性造血，与死亡率、血液恶性肿瘤、ASCVD 及相关疾病的风险增加有关。值得注意的是，许多表现出克隆性造血的个体携带 preleukemic 基因中的单个“驱动”突变，包括 DNA 甲基转移酶 3a、ten-eleven translocation 2、额外的性梳 1 和 Janus 激酶 2。实验研究表明，这些基因中的一些突变可以改变白细胞的炎症特性，并有助于 ASCVD 的发病机制。
我们通过关注常见的驱动基因突变，综述了最近关于与年龄相关的克隆性造血与 ASCVD 之间关联的流行病学和实验研究结果。
