不确定潜能的克隆性造血与腹主动脉瘤的发生有关。
Clonal Hematopoiesis of Indeterminate Potential Is Associated With Incident Abdominal Aortic Aneurysm.
作者信息
Tan Yu, Zhu Xuanmeng, Huang Yuanfeng, Zhao Chenxuan, Cheng Xunjie, Li Jinchen, Zhang Guogang, Ma Tianqi, Yang Shujun, Bai Yongping
机构信息
Department of Cardiovascular Medicine (Y.T., X.Z., C.Z., X.C., G.Z., T.M., S.Y.), Xiangya Hospital, Central South University, Changsha, China.
Center of Coronary Circulation (Y.T., X.Z., C.Z., X.C., G.Z., T.M., S.Y.), Xiangya Hospital, Central South University, Changsha, China.
出版信息
Arterioscler Thromb Vasc Biol. 2025 Jul;45(7):1326-1336. doi: 10.1161/ATVBAHA.124.322630. Epub 2025 May 8.
BACKGROUND
Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging risk factor for cardiovascular diseases. Genetic IL (interleukin)-6 signaling deficiency reduced cardiovascular disease risk in CHIP carriers. However, the association between CHIP and incident abdominal aortic aneurysm (AAA) and whether IL-6 signaling inhibition attenuates AAA risk among individuals with CHIP remained unclear.
METHODS
Participants without prevalent AAA from the UK Biobank were included. The associations of any CHIP (variant allele fraction, ≥2%), large CHIP (variant allele fraction, ≥10%), and gene-specific CHIP subtypes with incident AAA were investigated. The protection role of p.Asp358Ala, a genetic proxy for IL-6 deficiency, was tested after stratification by CHIP status. Furthermore, the interaction and joint effects of CHIP and genetic susceptibility on AAA risk were tested.
RESULTS
This study included 425 211 participants. Any CHIP and large CHIP was identified in 13 768 (3.2%) and 8576 (2.0%) participants, respectively. CHIP was associated with an increased risk of incident AAA (hazard ratio [HR], 1.21 [95% CI, 1.01-1.44]; =0.034), with large CHIP clones exhibiting greater effect size (HR, 1.35 [95% CI, 1.10-1.66]; =0.0045). Driver gene-specific analyses revealed that -mediated CHIP exerted the strongest effect size on AAA risk (HR, 2.10 [95% CI, 1.54-2.88]; <0.001). The presence of 2 p.Asp358Ala alleles attenuated the risk of AAA in large CHIP carriers (HR, 0.48 [95% CI, 0.23-0.99]; =0.046). In the joint analysis, participants with CHIP and high genetic risk had a higher risk of developing AAA than those without CHIP and with low genetic risk (HR, 2.15 [95% CI, 1.63-2.85]; <0.001).
CONCLUSIONS
CHIP is associated with an increased risk of AAA. Genetic IL-6 signaling deficiency attenuates the risk of AAA in large CHIP carriers. CHIP may serve as an attractive target for the prevention and treatment of AAA.
背景
不确定潜能的克隆性造血（CHIP）是心血管疾病新出现的一个风险因素。遗传性白细胞介素（IL）-6信号缺陷降低了CHIP携带者患心血管疾病的风险。然而，CHIP与腹主动脉瘤（AAA）发病之间的关联，以及IL-6信号抑制是否能降低CHIP个体发生AAA的风险仍不明确。
方法
纳入英国生物银行中无AAA病史的参与者。研究了任何CHIP（变异等位基因频率≥2%）、大CHIP（变异等位基因频率≥10%）以及基因特异性CHIP亚型与AAA发病的关联。在按CHIP状态分层后，检测了p.Asp358Ala（一种IL-6缺乏的遗传替代指标）的保护作用。此外，还检测了CHIP与遗传易感性对AAA风险的相互作用和联合效应。
结果
本研究纳入425211名参与者。分别在13768名（3.2%）和8576名（2.0%）参与者中检测到任何CHIP和大CHIP。CHIP与AAA发病风险增加相关（风险比[HR]，1.21[95%CI，1.01 - 1.44]；P = 0.034），大CHIP克隆显示出更大的效应量（HR，1.35[95%CI，1.10 - 1.66]；P = 0.0045）。驱动基因特异性分析显示，JAK2介导的CHIP对AAA风险的效应量最强（HR，2.10[95%CI，1.54 - 2.88]；P < 0.001）。携带2个p.Asp358Ala等位基因可降低大CHIP携带者发生AAA的风险（HR, 0.48[95%CI，0.23 - 0.99]；P = 0.046）。在联合分析中，有CHIP且遗传风险高的参与者发生AAA的风险高于无CHIP且遗传风险低的参与者（HR，2.15[95%CI，1.63 - 2.85]；P < 0.001）。
结论
CHIP与AAA风险增加相关。遗传性IL-6信号缺陷可降低大CHIP携带者发生AAA的风险。CHIP可能是预防和治疗AAA的一个有吸引力的靶点。
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