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

doi:10.1016/j.ebiom.2022.103964

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

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Abstract

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.

Original language	English
Article number	103964
Pages (from-to)	103964
Journal	EBioMedicine
Volume	78
DOIs	https://doi.org/10.1016/j.ebiom.2022.103964
Publication status	Published - Apr 2022

Bibliographical note

Funding Information:
We gratefully acknowledge the participants who provided biological samples and data for this analysis. This work was supported by National Natural Science Foundation of China (Grant Nos.: 81722025 , 82061130223 , and 81827806 ); and National Key R&D Program of China (Grant Nos.: 2016YFC1301101 and 2016YFC1301103).

Publisher Copyright:
© 2022 The Author(s)

Keywords

Clonal Hematopoiesis
Cytokines
DNA Methyltransferase 3A/genetics
DNA-Binding Proteins/genetics
Dioxygenases/genetics
Humans
Mutation
Prevalence
Prognosis
Proto-Oncogene Proteins/genetics
ST Elevation Myocardial Infarction/diagnosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wang, S., Hu, S., Luo, X., Bao, X., Li, J., Liu, M., Lv, Y., Zhao, C., Zeng, M., Chen, X., Unsworth, A., Jones, S., Johnson, T. W., White, S. J., Jia, H., & Yu, B. (2022). Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction. EBioMedicine, 78, 103964. Article 103964. https://doi.org/10.1016/j.ebiom.2022.103964

@article{2662870e9cb941b293253f27806b7bac,

title = "Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction",

abstract = "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.",

keywords = "Clonal Hematopoiesis, Cytokines, DNA Methyltransferase 3A/genetics, DNA-Binding Proteins/genetics, Dioxygenases/genetics, Humans, Mutation, Prevalence, Prognosis, Proto-Oncogene Proteins/genetics, ST Elevation Myocardial Infarction/diagnosis",

author = "Shengfang Wang and Sining Hu and Xing Luo and Xiaoyi Bao and Ji Li and Minghao Liu and Ying Lv and Chen Zhao and Ming Zeng and Xi Chen and Amanda Unsworth and Sarah Jones and Johnson, {Thomas W} and White, {Stephen J} and Haibo Jia and Bo Yu",

note = "Funding Information: We gratefully acknowledge the participants who provided biological samples and data for this analysis. This work was supported by National Natural Science Foundation of China (Grant Nos.: 81722025 , 82061130223 , and 81827806 ); and National Key R&D Program of China (Grant Nos.: 2016YFC1301101 and 2016YFC1301103). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = apr,

doi = "10.1016/j.ebiom.2022.103964",

language = "English",

volume = "78",

pages = "103964",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Amsterdam:Elsevier",

}

Wang, S, Hu, S, Luo, X, Bao, X, Li, J, Liu, M, Lv, Y, Zhao, C, Zeng, M, Chen, X, Unsworth, A, Jones, S, Johnson, TW, White, SJ, Jia, H & Yu, B 2022, 'Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction', EBioMedicine, vol. 78, 103964, pp. 103964. https://doi.org/10.1016/j.ebiom.2022.103964

TY - JOUR

T1 - Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction

AU - Wang, Shengfang

AU - Hu, Sining

AU - Luo, Xing

AU - Bao, Xiaoyi

AU - Li, Ji

AU - Liu, Minghao

AU - Lv, Ying

AU - Zhao, Chen

AU - Zeng, Ming

AU - Chen, Xi

AU - Unsworth, Amanda

AU - Jones, Sarah

AU - Johnson, Thomas W

AU - White, Stephen J

AU - Jia, Haibo

AU - Yu, Bo

N1 - Funding Information: We gratefully acknowledge the participants who provided biological samples and data for this analysis. This work was supported by National Natural Science Foundation of China (Grant Nos.: 81722025 , 82061130223 , and 81827806 ); and National Key R&D Program of China (Grant Nos.: 2016YFC1301101 and 2016YFC1301103). Publisher Copyright: © 2022 The Author(s)

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - Clonal Hematopoiesis

KW - Cytokines

KW - DNA Methyltransferase 3A/genetics

KW - DNA-Binding Proteins/genetics

KW - Dioxygenases/genetics

KW - Humans

KW - Mutation

KW - Prevalence

KW - Prognosis

KW - Proto-Oncogene Proteins/genetics

KW - ST Elevation Myocardial Infarction/diagnosis

U2 - 10.1016/j.ebiom.2022.103964

DO - 10.1016/j.ebiom.2022.103964

M3 - Article (Academic Journal)

C2 - 35339897

SN - 2352-3964

VL - 78

SP - 103964

JO - EBioMedicine

JF - EBioMedicine

M1 - 103964

ER -

Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction

Abstract

Bibliographical note

Keywords

UN SDGs

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