Molecular determinants of thrombosis recurrence risk across venous thromboembolism subtypes
Abstract
Abstract Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1000 individuals) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within 5 years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding. We analyzed the genomic architecture of VTE recurrence using data from 6355 patients across 8 cohorts (including 1775 recurrences), enriched by subgroup analyses, according to sex and clinical manifestation of first VTE, which led to the identification of 28 molecular markers. Through genome-wide association studies, we identified 1 locus associated with VTE recurrence, GPR149/MME. Among all variants known to be associated with first VTE, KNG1, and FGG were associated with recurrence. Additionally, Mendelian randomization analyses identified 7 proteins as risk factors for recurrence: elevated plasma levels of coagulation factor XI, coagulation factor VIII, von Willebrand factor, histo-blood group ABO system transferase, and Golgi membrane protein 2; and decreased levels of proprotein convertase subtilisin/kexin 9 and pro–interleukin-16. Subgroup analyses revealed 18 molecular determinants associated with VTE recurrence, with notable differences between subgroups. For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated in patients who experienced pulmonary embolism but showed no effect in those with deep vein thrombosis. These findings emphasize the role of specific genetic loci and protein pathways in influencing VTE recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.
Article Details
Authors (34)
Gaëlle Munsch
1University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
Florian Thibord
INSERM UMR 1219, Bordeaux Population Health Research Center, Bordeaux, France (F.T.).
Ohanna C. Bezerra
4Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Jennifer A. Brody
Astrid van Hylckama Vlieg
6Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Lénaïck Gourhant
7University of Brest, INSERM, UMR 1304, Groupe d'étude de la Thrombose de Bretagne Occidentale, Brest, France
Ming-Huei Chen
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham, MA
Floriane Samaria
1University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
Marine Germain
1University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
Ilana Caro
1University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
Pierre Suchon
8Cardiovascular and Nutrition Research Center, INSERM, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement, Aix-Marseille University, Marseille, France
Robert Olaso
Kerri L. Wiggins
Noémie Saut
8Cardiovascular and Nutrition Research Center, INSERM, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement, Aix-Marseille University, Marseille, France
Céline Besse
Louisa Goumidi
8Cardiovascular and Nutrition Research Center, INSERM, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement, Aix-Marseille University, Marseille, France
Delphine Bacq
10Université Paris-Saclay, Commissariat à l'énergie atomique et aux énergies alternatives, Centre National de Recherche en Génomique Humaine, Evry, France
Laura B. Harrington
11Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA
Anne Boland
Joseph Emmerich
14Department of Vascular Medicine, Paris Saint-Joseph Hospital Group, Université Paris Cité, UMR1153, INSERM, Centre de Recherche en Épidémiologie et Statistiques, Paris, France
David M. Smadja
Catherine A. Lemarié
7University of Brest, INSERM, UMR 1304, Groupe d'étude de la Thrombose de Bretagne Occidentale, Brest, France
Sven Danckwardt
16Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
Stephanie Debette
Jean-François Deleuze
Hélène Jacqmin-Gadda
1University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
Marc A. Rodger
19Department of Medicine, McGill University, Montreal, QC, Canada
France Gagnon
4Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Frits R. Rosendaal
Andrew D. Johnson
Nicholas L. Smith
Francis Couturaud
Investigation Network on Venous Thrombo-Embolism–French Clinical Research Infrastructure Network, Saint-Étienne, France
Pierre-Emmanuel Morange
David-Alexandre Trégouët