TERT and TET2 Genetic Variants Affect Leukocyte Telomere Length and Clinical Outcome in Coronary Artery Disease Patients-A Possible Link to Clonal Hematopoiesis

Trine B Opstad; Svein Solheim; Alf-Åge R Pettersen; Are A Kalstad; Harald Arnesen; Ingebjørg Seljeflot

doi:10.3390/biomedicines10082027

TERT and TET2 Genetic Variants Affect Leukocyte Telomere Length and Clinical Outcome in Coronary Artery Disease Patients-A Possible Link to Clonal Hematopoiesis

Biomedicines. 2022 Aug 19;10(8):2027. doi: 10.3390/biomedicines10082027.

Authors

Trine B Opstad^{1

2}, Svein Solheim¹, Alf-Åge R Pettersen¹, Are A Kalstad¹, Harald Arnesen^{1

2}, Ingebjørg Seljeflot^{1

2}

Affiliations

¹ Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Kirkeveien 166, Pb 4950 Nydalen, N-0240 Oslo, Norway.
² Faculty of Medicine, University of Oslo, 0315 Oslo, Norway.

Abstract

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.

Keywords: TERT; TET2; clonal hematopoiesis; genetic variation; telomere.

Grants and funding

This research was funded by the Norwegian Council for Cardiovascular Diseases and Stein Erik Hagen Foundation for Clinical Heart Research, Oslo Norway.