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

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.

Figure 1

Association of the TERT rs7705526 mutation with MACE in certain subcategories. Tables underneath each figure denote actual numbers in different groups. (a) Frequency of TERT rs7705526 (C/A) homozygous subjects (AA) according to major clinical events (MACEs), separated by gender. Black and gray columns represent the % of AA homozygous without and with MACE, respectively. (b) Frequency of TERT rs7705526 (C/A) homozygous subjects (AA) according to acute myocardial infarction (AMI), separated by gender. Black columns represent the % of AA homozygous without AMI in both gender. The gray columns represent the % of AA homozygous suffering from AMI in men and women, respectively. (c) Frequency of TERT rs7705526 (C/A) homozygous subjects (AA) according to stroke, separated by gender. Black columns represent the % of AA homozygous patients without stroke. The gray columns represent the % of AA homozygous suffering from strokes in women and men, respectively.

Figure 2

Relatively quantified (RQ) leukocyte telomere length (LTL), related to TERT rs7705526 (C/A) and TET2 rs2454206 (A/G) genotypes. p¹ values refer to the difference in LTLs between genotypes, whereas p² values refer to differences in LTLs between the presence of the variant allele compared to the wild type. In this subset, LTLs were not associated with MACE (n = 34), independent of TERT and TET2 genotypes (median RQ level (25, 75 percentiles): 0.67 (0.51, 0.91) as compared to without MACE (n = 228): 0.61 (0.46, 0.96)).