| Summary: | 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 (<i>p</i> = 0.004), acute myocardial infarction (AMI) in male patients (<i>p</i> = 0.011), and stroke in female patients (<i>p</i> < 0.001). Mutated TET2 correlated with type 2 diabetes (<i>p</i> < 0.001), the metabolic syndrome (<i>p</i> = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (<i>p</i> = 0.032, <i>p</i> = 0.003, and <i>p</i> = 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.
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