在出现 ST 段抬高型心肌梗死的患者中，DNMT3A 和 TET2 驱动突变的克隆性造血的流行率和预后意义。

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

机构信息

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.

Department of Life Sciences, Manchester Metropolitan University, Manchester M1 5GD, UK.

出版信息

EBioMedicine. 2022 Apr;78:103964. doi: 10.1016/j.ebiom.2022.103964. Epub 2022 Mar 24.

DOI:10.1016/j.ebiom.2022.103964

PMID:35339897

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8960977/

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.

摘要

背景

最近发现，DNMT3A 或 TET2 突变驱动的克隆性造血作用是心血管疾病的一个新的风险因素。实验研究表明，这些突变可能增强炎症，从而加速疾病进展。我们旨在研究 DNMT3A 和 TET2 突变的发生率及其与 ST 段抬高型心肌梗死（STEMI）患者预后的关系。

方法

对 485 例 STEMI 患者进行了靶向深度测序以检测 DNMT3A 和 TET2 以及炎症细胞因子（IL-1β、IL-6、TNF-α、INF-γ）。主要不良心脏事件（MACE）是死亡、心肌梗死、卒中和因心力衰竭住院的复合终点。

结果

在 485 例 STEMI 患者中，发现携带 DNMT3A 或 TET2-CH 驱动突变且等位基因变异频率（VAF）≥2%的患者占 12.4%（60 例），与未携带突变的患者相比，这些患者的死亡率（30.9%比 15.5%，P=0.001）和 MACE 发生率（44.5%比 21.8%，P<0.001）更高。在中位随访 3.0 年（四分位距：2.4-3.4）期间。在校正混杂因素后，突变仍然是死亡（HR=1.967，95%CI 1.103-3.507，P=0.022）和 MACE（HR=1.833，95%CI 1.154-2.912，P=0.010）的独立预测因素。DNMT3A/TET2 VAF≥2%组患者的血浆 IL-1β（P=0.010）和 IL-6（P=0.011）浓度显著升高。