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
Ohanna C.L. Bezerra , Marc Rodger , Gaëlle Munsch , Michael J. Kovacs , Grégoire Le Gal , Pierre-Emmanuel Morange , David-Alexandre Trégouët , Celia M.T. Greenwood , France Gagnon
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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 underlie this sex-biased rVTE risk difference.

Objectives

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 a 5-year follow-up (REcurrent VEnous thromboembolism Risk Stratification Evaluation [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 a 14-year follow-up (the MARseille THrombosis Association [MARTHA]), to investigate whether DNAm is a risk factor 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 < 7x10−8). 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 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.

Conclusion

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