Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction
Shengfang Wang,
Sining Hu,
Xing Luo,
Xiaoyi Bao,
Ji Li,
Minghao Liu,
Ying Lv,
Chen Zhao,
Ming Zeng,
Xi Chen,
Amanda Unsworth,
Sarah Jones,
Thomas W. Johnson,
Stephen J. White,
Haibo Jia,
Bo Yu
Affiliations
Shengfang Wang
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Sining Hu
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Xing Luo
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Xiaoyi Bao
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Ji Li
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Minghao Liu
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Ying Lv
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Chen Zhao
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Ming Zeng
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Xi Chen
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China
Amanda Unsworth
Department of Life Sciences, Manchester Metropolitan University, Manchester M1 5GD, UK
Sarah Jones
Department of Life Sciences, Manchester Metropolitan University, Manchester M1 5GD, UK
Thomas W. Johnson
Department of Cardiology, Bristol Heart Institute, Upper Maudlin St., Bristol BS2 8HW, UK
Stephen J. White
Department of Life Sciences, Manchester Metropolitan University, Manchester M1 5GD, UK
Haibo Jia
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China; Corresponding authors at: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
Bo Yu
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China; The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China; Corresponding authors at: Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
Summary: Background: Clonal haematopoiesis driven by mutations in DNMT3A or TET2 has recently been identified as a new risk factor for cardiovascular disease. Experimental studies suggest that these mutations may enhance inflammation which accelerates the disease progression. We aim to investigate the prevalence of mutations in DNMT3A and TET2 and their association with prognosis of patients with ST-segment elevation myocardial infarction (STEMI). Methods: Targeted deep sequencing for DNMT3A and TET2 and inflammatory cytokines (IL-1β, IL-6, TNF-α, INF-γ) were analyzed in 485 patients with STEMI. Major adverse cardiac events (MACE) was a composite of death, myocardial infarction, stroke, or hospitalization due to heart failure. Findings: Patients carrying DNMT3A- or TET2-CH-driver mutations with a variant allele frequency (VAF) ≥2% were found in 12.4% (60 of 485) of STEMI patients and experienced an increased incidence of the death (30.9% vs 15.5%, P = 0.001) and MACE (44.5% vs 21.8%, P < 0.001) compared to those who did not, during a median follow up of 3.0 (interquartile range: 2.4–3.4) years. After adjusting for confounders, mutation remained an independent predictor of death (HR = 1.967, 95% CI 1.103–3.507, P = 0.022) and MACE (HR = 1.833, 95% CI 1.154–2.912, P = 0.010). Concentrations of plasma IL-1β (P = 0.010) and IL-6 (P = 0.011) were significantly elevated in DNMT3A/TET2 VAF≥2% group. Interpretation: DNMT3A- or TET2-CH-driver mutations with a VAF≥2% were observed in over 10% STEMI patients, and were significantly associated with poorer prognosis, which might be explained by higher levels of inflammatory cytokines in mutations carriers. Funding: National Natural Science Foundation of China; National Key R&D Program of China.
