Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.
Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.
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DOI：
10.1056/nejmoa1701719
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发表时间：
2017-07-13
期刊：
影响因子：
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通讯作者：
Ebert BL
中科院分区：
文献类型：
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作者：
Jaiswal S;Natarajan P;Silver AJ;Gibson CJ;Bick AG;Shvartz E;McConkey M;Gupta N;Gabriel S;Ardissino D;Baber U;Mehran R;Fuster V;Danesh J;Frossard P;Saleheen D;Melander O;Sukhova GK;Neuberg D;Libby P;Kathiresan S;Ebert BL
不确定潜能的克隆性造血（CHIP），定义为在没有其他血液学异常的人中存在扩增的体细胞克隆，在老年人中很常见，并与发生血液学癌症的风险增加有关。我们先前发现了CHIP与人类动脉粥样硬化性心血管疾病相关的初步证据，但这种关联的性质尚不清楚。我们使用全外显子组测序来检测外周血细胞中CHIP的存在，并在4项病例对照研究中将其与冠心病联系起来，这些研究共包括4，794例病例和3，537例对照。为了评估因果关系，我们扰乱了Tet2的功能，Tet2是与克隆造血相关的第二个最常见的突变基因，在动脉粥样硬化易感小鼠的造血细胞中。在两个前瞻性队列的巢式病例对照分析中，CHIP携带者与非携带者相比，冠心病风险增加1.9倍（95%置信区间1.4 - 2.7）。在两个早发性心肌梗死的回顾性病例对照队列中，CHIP患者发生心肌梗死的风险高4.0倍（95%置信区间2.4 - 6.7）。DNMT3A、TET2、ASXL1和JAK2的突变分别与冠心病相关。克隆性造血患者的冠状动脉钙化也增加，这是冠状动脉粥样硬化负荷的标志。与接受对照骨髓的小鼠相比，接受Tet2 −/−或Tet2 +/−骨髓移植的高脂血症小鼠在主动脉根部和主动脉中发生了更大的动脉粥样硬化病变。Tet2 −/−巨噬细胞的分析表明，几种趋化因子和细胞因子基因的表达升高，导致动脉粥样硬化。克隆性造血与人类冠心病密切相关，并导致小鼠动脉粥样硬化加速。
Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of an expanded somatic blood cell clone in those without other hematologic abnormalities, is common in older individuals and associates with an increased risk of developing hematologic cancer. We previously found preliminary evidence for an association of CHIP with human atherosclerotic cardiovascular disease, but the nature of this association was unclear. We used whole exome sequencing to detect the presence of CHIP in peripheral blood cells and associated this with coronary heart disease in four case-control studies together comprising 4,794 cases and 3,537 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. In nested case-control analyses from two prospective cohorts, carriers of CHIP had a 1.9-fold (95% confidence interval 1.4–2.7) increased risk of coronary heart disease compared to non-carriers. In two retrospective case-control cohorts for early-onset myocardial infarction, those with CHIP had a 4.0-fold greater risk (95% confidence interval 2.4–6.7) of having myocardial infarction. Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. Those with clonal hematopoiesis also had increased coronary artery calcification, a marker of coronary atherosclerosis burden. Hyperlipidemic mice engrafted with Tet2−/− or Tet2+/− bone marrow developed larger atherosclerotic lesions in the aortic root and aorta than mice receiving control marrow. Analyses of Tet2−/− macrophages demonstrated elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. Clonal hematopoiesis robustly associates with coronary heart disease in humans and causes accelerated atherosclerosis in mice.