Clonal hematopoiesis of indeterminate potential (CHIP), marked by the accumulation of somatic mutations in hematopoietic stem cells, significantly elevates the risk of all-cause mortality, mainly due to cardiovascular events. Therefore, investigating this pathophysiological phenomenon is crucial for understanding cardiovascular aging and enhancing both health span and lifespan. In the present study, we examined samples of subjects enrolled within the angiographically controlled Verona Heart Study (VHS), which provides a robust model for cardiovascular aging, particularly regarding coronary artery disease (CAD). We analyzed 44 older subjects diagnosed with coronary artery disease (CAD) and 42 healthy, sex- and age-matched controls (CAD-FREE). Employing deep sequencing and an amplicon-based approach, we focused on 11 key genetic regions in ASXL1, DNMT3A, IDH1, IDH2, JAK2, PPM1D, SF3B1, SRSF2, TET2, TP53, and U2AF1 genes to investigate clonal hematopoiesis. Subjects in the CAD group exhibited a significantly higher variant burden than those in the CAD-FREE group, both in terms of the total number of somatic variants and disruptive variants affecting protein function. This increased mutational load was notably influenced by six specific genetic regions: ASXL1, DNMT3A, IDH2, JAK2, TET2, and U2AF1, which displayed elevated variant rates in the CAD subjects. Moreover, ASXL1, DNMT3A, IDH2, JAK2, SF3B1, TET2, and TP53 exhibited substantially higher levels of disruptive variants in the CAD group. In summary, our findings highlight a correlation between clonal hematopoiesis and the accumulation of disruptive variants in specific genomic regions in the VHS cohort, thereby shedding light on their potential role in cardiovascular aging.

不确定电位克隆造血 （CHIP） 以造血干细胞中体细胞突变的积累为标志，显著增加了主要由心血管事件引起的全因死亡风险。因此，研究这种病理生理现象对于了解心血管衰老和提高健康寿命至关重要。在本研究中，我们检查了血管造影控制维罗纳心脏研究 （VHS） 中登记的受试者样本，该研究为心血管衰老提供了一个强大的模型，特别是关于冠状动脉疾病 （CAD）。我们分析了 44 名被诊断患有冠状动脉疾病 （CAD） 的老年受试者和 42 名健康、性别和年龄匹配的对照 （CAD-FREE）。采用深度测序和基于扩增子的方法，我们专注于 ASXL1 、 DNMT3A 、 IDH1 、 IDH2 、 JAK2 、 PPM1D 、 SF3B1 、 SRSF2 、 TET2 、 TP53 和 U2AF1 基因中的 11 个关键遗传区域，以研究克隆造血。CAD 组的受试者在体细胞变异的总数和影响蛋白质功能的破坏性变异的总数方面都表现出显著高于 CAD-FREE 组的变异负担。这种增加的突变负荷受到六个特定遗传区域的显着影响： ASXL1 、 DNMT3A 、 IDH2 、 JAK2 、 TET2 和 U2AF1 ，它们在 CAD 受试者中表现出升高的变异率。 此外，ASXL1 、 DNMT3A 、 IDH2 、 JAK2 、 SF3B1 、 TET2 和 TP53 在 CAD 组中表现出更高水平的破坏性变异。总之，我们的研究结果强调了克隆造血与 VHS 队列中特定基因组区域中破坏性变异积累之间的相关性，从而阐明了它们在心血管衰老中的潜在作用。