克隆性造血与动脉粥样硬化性心血管疾病风险
Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.
作者信息
Jaiswal Siddhartha, Natarajan Pradeep, Silver Alexander J, Gibson Christopher J, Bick Alexander G, Shvartz Eugenia, McConkey Marie, Gupta Namrata, Gabriel Stacey, Ardissino Diego, Baber Usman, Mehran Roxana, Fuster Valentin, Danesh John, Frossard Philippe, Saleheen Danish, Melander Olle, Sukhova Galina K, Neuberg Donna, Libby Peter, Kathiresan Sekar, Ebert Benjamin L
机构信息
From the Department of Medicine, Division of Hematology, Brigham and Women's Hospital (S.J., A.J.S., M.M.) and Harvard Medical School (B.L.E.), the Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital (E.S.) and Harvard Medical School (G.K.S., P.L.), the Department of Pathology (S.J.) and the Center for Genomic Medicine (P.N., S.K.), Massachusetts General Hospital, the Department of Medicine, Division of Cardiology, and Cardiovascular Research Center (P.N., S.K.), and the Department of Medicine (A.G.B.), Massachusetts General Hospital and Harvard Medical School, and the Departments of Medical Oncology (C.J.G.) and Biostatistics and Computational Biology (D.N.), Dana-Farber Cancer Institute, Boston, and the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., A.G.B., N.G., S.G., S.K.) - all in Massachusetts; the Department of Cardiology, University Hospital, Parma, Italy (D.A.); the Department of Medicine, Division of Cardiology, Mt. Sinai School of Medicine, New York (U.B., R.M., V.F.); Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid (V.F.); Medical Research Council-British Heart Foundation Cardiovascular Epidemiology Unit and National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, and the British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge (J.D.), and the Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (J.D.) - both in the United Kingdom; the Center for Non-Communicable Diseases, Karachi, Pakistan (P.F., D.S.); the Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia (D.S.); and the Department of Clinical Sciences Malmö, Lund University, Lund, Sweden (O.M.).
出版信息
N Engl J Med. 2017 Jul 13;377(2):111-121. doi: 10.1056/NEJMoa1701719. Epub 2017 Jun 21.
BACKGROUND
Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.
METHODS
We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.
RESULTS
In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.
CONCLUSIONS
The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).
背景
不确定潜能的克隆性造血（CHIP）被定义为在无其他血液学异常的个体中存在一个扩增的体细胞血细胞克隆，在老年人中很常见，并且与血液系统癌症风险增加相关。我们之前发现了CHIP与动脉粥样硬化性心血管疾病之间存在关联的初步证据，但这种关联的性质尚不清楚。
方法
我们使用全外显子测序来检测外周血细胞中CHIP的存在，并使用来自四项病例对照研究的样本，将其存在情况与冠心病相关联，这四项研究共纳入了4726例冠心病患者和3529例对照。为了评估因果关系，我们在易患动脉粥样硬化的小鼠的造血细胞中干扰了Tet2的功能，Tet2是与克隆性造血相关的第二常见突变基因。
结果
在两项前瞻性队列的巢式病例对照分析中，CHIP携带者患冠心病的风险是非携带者的1.9倍（95%置信区间[CI]，1.4至2.7）。在两项用于评估早发性心肌梗死的回顾性病例对照队列中，CHIP参与者患心肌梗死的风险是非携带者的4.0倍（95%CI，2.4至6.7）。DNMT3A、Tet2、ASXL1和JAK2的突变各自均与冠心病相关。携带这些突变的CHIP携带者的冠状动脉钙化也增加，冠状动脉钙化是冠状动脉粥样硬化负担的一个标志物。移植了来自纯合或杂合Tet2基因敲除小鼠的骨髓的易患高胆固醇血症的小鼠，其主动脉根部和主动脉的动脉粥样硬化病变比接受对照骨髓的小鼠更大。对Tet2基因敲除小鼠的巨噬细胞分析显示，几种促成动脉粥样硬化的趋化因子和细胞因子基因的表达升高。
结论
外周血细胞中CHIP的存在与人类冠心病风险增加近一倍以及小鼠动脉粥样硬化加速相关。（由美国国立卫生研究院等资助。）
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