Sex-specific DNA methylation marks associated with sex-biased risk of recurrence in unprovoked venous thromboembolism.

IF 5.5 2区医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2025-01-21 DOI:10.1016/j.jtha.2025.01.004

Ohanna C L Bezerra, Marc Rodger, Gaëlle Munsch, Michael J Kovacs, Grégoire Le Gal, Pierre E Morange, David-Alexandre Trégouët, Celia M T Greenwood, France Gagnon

{"title":"Sex-specific DNA methylation marks associated with sex-biased risk of recurrence in unprovoked venous thromboembolism.","authors":"Ohanna C L Bezerra, Marc Rodger, Gaëlle Munsch, Michael J Kovacs, Grégoire Le Gal, Pierre E Morange, David-Alexandre Trégouët, Celia M T Greenwood, France Gagnon","doi":"10.1016/j.jtha.2025.01.004","DOIUrl":null,"url":null,"abstract":"Background: Whether to stop oral anticoagulants after a first unprovoked venous thromboembolism (VTE) is challenging, partially due to an intriguingly higher risk of VTE recurrence (rVTE) in men after therapy discontinuation. DNA methylation (DNAm) differences between men and women might underly this sex-biased rVTE risk difference.Aim: To investigate sex-specific associations between DNAm at cytosine-phosphate-guanine (CpG) sites and rVTE.Methods: In 417 unprovoked VTE patients, including 101 experiencing recurrences over 5-year follow-up (REVERSE I), we analyzed blood DNAm using the Illumina EPIC array and performed a sex-stratified epigenome-wide association study. We further examined 181 major provoked VTE patients, including 36 recurrences over 14-year follow-up (MARTHA), to investigate whether DNAm are risk factors for rVTE after anticoagulation therapy.Results: Hypomethylated CpGs at genes TBC1D22B-cg01060850 and ZHX2-cg07808424 in men and DIP2B-ch.12.1038646R and DENND3-cg03401656 in women were associated with rVTE at genome-wide level (p<7e-8). Though not statistically significant, DENND3-cg03401656 had the same direction of effect in MARTHA women. Sensitivity analysis confirmed the robustness of the estimates including potential confounders, adaptations of the Cox model, non-Europeans, and proximal methylation quantitative trait loci (meQTLs) in the association. The associated CpGs were situated at genes for membrane trafficking, corroborating the participation of Rab regulatory proteins in rVTE, and transcription factors.Conclusions: We identified DNAm marks as potential risk factors for sex-biased recurrence in unprovoked VTE. Further replication and experimental validation could refine our understanding on the regulation of the identified DNAm sites and help optimize personalized decision-making for long-term anticoagulation after first VTE.","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5000,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thrombosis and Haemostasis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtha.2025.01.004","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Whether to stop oral anticoagulants after a first unprovoked venous thromboembolism (VTE) is challenging, partially due to an intriguingly higher risk of VTE recurrence (rVTE) in men after therapy discontinuation. DNA methylation (DNAm) differences between men and women might underly this sex-biased rVTE risk difference.

Aim: To investigate sex-specific associations between DNAm at cytosine-phosphate-guanine (CpG) sites and rVTE.

Methods: In 417 unprovoked VTE patients, including 101 experiencing recurrences over 5-year follow-up (REVERSE I), we analyzed blood DNAm using the Illumina EPIC array and performed a sex-stratified epigenome-wide association study. We further examined 181 major provoked VTE patients, including 36 recurrences over 14-year follow-up (MARTHA), to investigate whether DNAm are risk factors for rVTE after anticoagulation therapy.

Results: Hypomethylated CpGs at genes TBC1D22B-cg01060850 and ZHX2-cg07808424 in men and DIP2B-ch.12.1038646R and DENND3-cg03401656 in women were associated with rVTE at genome-wide level (p<7e-8). Though not statistically significant, DENND3-cg03401656 had the same direction of effect in MARTHA women. Sensitivity analysis confirmed the robustness of the estimates including potential confounders, adaptations of the Cox model, non-Europeans, and proximal methylation quantitative trait loci (meQTLs) in the association. The associated CpGs were situated at genes for membrane trafficking, corroborating the participation of Rab regulatory proteins in rVTE, and transcription factors.

Conclusions: We identified DNAm marks as potential risk factors for sex-biased recurrence in unprovoked VTE. Further replication and experimental validation could refine our understanding on the regulation of the identified DNAm sites and help optimize personalized decision-making for long-term anticoagulation after first VTE.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

求助全文

约1分钟内获得全文去求助

来源期刊

Journal of Thrombosis and Haemostasis 医学-外周血管病

CiteScore

24.30

自引率

3.80%

发文量

321

审稿时长

1 months

期刊介绍： The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.