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与炎症和克隆造血相关的心血管风险的遗传修饰

Zhi Yu^1,2, Trevor P Fidler³, Yunfeng Ruan¹

¹Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

The Journal of clinical investigation

|July 27, 2023

概括

不确定潜力的克隆性血液形成 (CHIP) 增加了心血管疾病 (CVD) 的风险,可能是通过炎症酶激活. 这项研究确定了修改这种风险的关键炎症组基因,建议在CHIP患者中针对心血管疾病预防采取有针对性的策略.

科学领域:

遗传学和基因组学在
心血管医学心血管医学
免疫学免疫学免疫学

背景情况:

不确定潜力的克隆性血液形成 (CHIP) 是一种与心血管疾病 (CVD) 风险增加相关的获得性疾病.
炎症酶激活是CHIP相关心血管疾病风险的潜在机制之一.

研究的目的:

研究炎症基因修饰剂在CHIP相关心血管疾病风险中的作用.
确定影响CHIP患者心血管疾病风险的特定炎酶相关基因.

主要方法:

分析了来自424,651名英国生物库参与者的全外体序列数据,以确定CHIP.
对26个炎症体相关基因的预测基因表达分数的开发.
模拟CHIP作为一个复合物和单个驱动基因 (DNMT3A,TET2,ASXL1,JAK2).
在体外研究中使用CRISPR诱导的Asxl1-突变的小鼠巨细胞.

主要成果:

鉴定出IL1RAP是影响CHIP相关心血管疾病风险的关键分子,涉及多个驱动基因.
增加AIM2基因表达与JAK2-和ASXL1-CHIP相关的心血管疾病风险增加有关.
Asxl1突变的巨细胞对AIM2激动反应的炎症反应加剧,DNA损伤增加,IL-10分泌增加,反映出心血管疾病保护作用.

结论:

炎症酶在CHIP相关的心血管疾病中起着重要作用.
特定的炎症基因,如AIM2和IL1RAP,是CHIP中心血管疾病风险的关键修饰者.
这些发现支持开发基因特异性治疗策略,以减轻CHIP中的心血管疾病风险.

关键词:

心脏病学心脏病学心血管疾病是什么心血管疾病遗传学遗传学是一个鼠标模型鼠标模型人口遗传学人口遗传学

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