Opstad Trine B, Solheim Svein, Pettersen Alf-Åge R, Kalstad Are A, Arnesen Harald, Seljeflot Ingebjørg
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Kirkeveien 166, Pb 4950 Nydalen, N-0240 Oslo, Norway.
Faculty of Medicine, University of Oslo, 0315 Oslo, Norway.
Biomedicines. 2022 Aug 19;10(8):2027. doi: 10.3390/biomedicines10082027.
Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme reverse transcriptase (TERT) (rs7705526) and the epigenetic regulator ten−eleven translocation 2 (TET2) (rs2454206), were investigated in 1001 patients with stable coronary artery disease (CAD) (mean age 62 years, 22% women), with regards to cardiovascular outcome, comorbidities, and leukocyte telomere length. Over 2 years, mutated TERT increased the risk two-fold for major clinical events (MACEs) in all patients (p = 0.004), acute myocardial infarction (AMI) in male patients (p = 0.011), and stroke in female patients (p < 0.001). Mutated TET2 correlated with type 2 diabetes (p < 0.001), the metabolic syndrome (p = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (p = 0.032, p = 0.003, and p = 0.016, respectively). In conclusion, our results from stable CAD patients highlight TERTs’ role in CVD, and underline TET2s’ role in the epigenetic regulation of lifestyle-related diseases.
造血干细胞中的遗传突变和获得性突变可导致克隆性扩增，增加心血管疾病（CVD）风险，这是一种具有不确定潜能的克隆性造血（CHIP）疾病。在1001例稳定型冠状动脉疾病（CAD）患者（平均年龄62岁，22%为女性）中，研究了两个与CHIP相关的基因组位点的遗传变异，即端粒酶基因端粒酶逆转录酶（TERT）（rs7705526）和表观遗传调节因子十 - 十一易位2（TET2）（rs2454206），涉及心血管结局、合并症和白细胞端粒长度。在两年多的时间里，TERT突变使所有患者发生主要临床事件（MACE）的风险增加两倍（p = 0.004），男性患者发生急性心肌梗死（AMI）的风险增加（p = 0.011），女性患者发生中风的风险增加（p < 0.001）。TET2突变与2型糖尿病（p < 0.001）、代谢综合征（p = 0.002）以及空腹血糖、糖化血红蛋白和较短端粒相关（分别为p = 0.032、p = 0.003和p = 0.016）。总之，我们对稳定型CAD患者的研究结果突出了TERT在CVD中的作用，并强调了TET2在生活方式相关疾病表观遗传调控中的作用。
