Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis
Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis
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DOI：
10.1161/circulationaha.119.044362
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发表时间：
2020-01-14
期刊：
影响因子：
37.8
通讯作者：
Natarajan, Pradeep
中科院分区：
文献类型：
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作者：
Bick, Alexander G.;Pirruccello, James P.;Natarajan, Pradeep
背景：不确定潜能克隆造血（CHIP）是指由于 DNMT3A 或 TET2 等基因获得性白血病突变而导致的造血干细胞克隆扩增。在人类中，CHIP 与流行的心肌梗塞有关。在小鼠中，CHIP 加速动脉粥样硬化并增加 IL-6/IL-1 β 表达，提出了 CHIP 携带者的 IL-6 通路拮抗作用可降低心血管疾病 (CVD) 风险的假设。方法：我们分析了英国生物库中 35 416 名没有流行 CVD 的个体的外显子序列，以确定患有 DNMT3A 或 TET2 CHIP 的参与者。我们使用 IL6R p.Asp358Ala 编码突变作为 IL-6 抑制的遗传代理。我们测试了 CHIP 状态与 CVD 事件（心肌梗塞、冠状动脉血运重建、中风或死亡）的关联，以及它是否被 IL6R p.Asp358Ala 修饰。结果：我们鉴定了 1079 名 (3.0%) 个体患有 CHIP，其中 432 名 (1.2%) 具有大克隆（等位基因比例 >10%）。在 6.9 年的中位随访期间，CHIP 与 CVD 事件风险增加相关（风险比，1.27 [95% CI，1.04-1.56]，P=0.019），大型 CHIP 克隆的风险更大（风险比，1.59 [95% CI，1.21-2.09]，P
Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1 beta expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk. Methods: We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with DNMT3A or TET2 CHIP. We used the IL6R p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by IL6R p.Asp358Ala. Results: We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04-1.56], P=0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21-2.09], P