Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-04-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422001487 |
| _version_ | 1818776332662734848 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shengfang Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T11:11:15Z |
| format | Article |
| id | doaj.art-3b3b2eb37cfc4104b727b7f38ab884bd |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-18T11:11:15Z |
| publishDate | 2022-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-3b3b2eb37cfc4104b727b7f38ab884bd2022-12-21T21:09:59ZengElsevierEBioMedicine2352-39642022-04-0178103964Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarctionShengfang Wang0Sining Hu1Xing Luo2Xiaoyi Bao3Ji Li4Minghao Liu5Ying Lv6Chen Zhao7Ming Zeng8Xi Chen9Amanda Unsworth10Sarah Jones11Thomas W. Johnson12Stephen J. White13Haibo Jia14Bo Yu15Department 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment of Life Sciences, Manchester Metropolitan University, Manchester M1 5GD, UKDepartment of Life Sciences, Manchester Metropolitan University, Manchester M1 5GD, UKDepartment of Cardiology, Bristol Heart Institute, Upper Maudlin St., Bristol BS2 8HW, UKDepartment of Life Sciences, Manchester Metropolitan University, Manchester M1 5GD, UKDepartment 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.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.http://www.sciencedirect.com/science/article/pii/S2352396422001487Clonal hematopoiesisMyocardial infarctionDNMT3A/TET2PrognosisInflammation |
| spellingShingle | 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 Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction EBioMedicine Clonal hematopoiesis Myocardial infarction DNMT3A/TET2 Prognosis Inflammation |
| title | Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction |
| title_full | Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction |
| title_fullStr | Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction |
| title_full_unstemmed | Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction |
| title_short | Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction |
| title_sort | prevalence and prognostic significance of dnmt3a and tet2 clonal haematopoiesis driver mutations in patients presenting with st segment elevation myocardial infarction |
| topic | Clonal hematopoiesis Myocardial infarction DNMT3A/TET2 Prognosis Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422001487 |
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