Genomic Landscape of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes.

Autor:	Munsch G; Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, F-33000 Bordeaux, France., Thibord F; Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.; The Framingham Heart Study, Boston University, Framingham, MA, USA., Bezerra OC; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada., Brody JA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle WA, USA., van Hylckama Vlieg A; Department of Clinical Epidemiology, Leiden university Medical Center, Leiden, the Netherlands., Gourhant L; Univ Brest, Inserm, UMR 1304, GETBO, Brest, France., Chen MH; Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.; The Framingham Heart Study, Boston University, Framingham, MA, USA., Germain M; Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, F-33000 Bordeaux, France., Caro I; Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, F-33000 Bordeaux, France., Suchon P; Cardiovascular and Nutrition Research Center (C2VN), INSERM, INRAE, Aix-Marseille University, Marseille, France.; Biogenopole, Hematology Laboratory, La Timone University Hospital of Marseille, 264 Rue Saint-Pierre, Marseille, 13385, France., Olaso R; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, France., Wiggins KL; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle WA, USA., Saut N; Cardiovascular and Nutrition Research Center (C2VN), INSERM, INRAE, Aix-Marseille University, Marseille, France.; Biogenopole, Hematology Laboratory, La Timone University Hospital of Marseille, 264 Rue Saint-Pierre, Marseille, 13385, France., Besse C; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, France., Goumidi L; Cardiovascular and Nutrition Research Center (C2VN), INSERM, INRAE, Aix-Marseille University, Marseille, France., Bacq D; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, France., Harrington LB; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA 98101, USA.; Department of Epidemiology, University of Washington, Seattle WA, USA.; Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA., Boland A; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, France., Lemarié CA; Univ Brest, Inserm, UMR 1304, GETBO, Brest, France., Danckwardt S; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.; Department for Clinical Chemistry and Laboratory Medicine, University Medical Center Ulm, Germany., Debette S; Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, F-33000 Bordeaux, France.; Bordeaux University Hospital, Department of Neurology, Institute for Neurodegenerative Diseases, F-33000, Bordeaux, France., Deleuze JF; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, France., Jacqmin-Gadda H; Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, F-33000 Bordeaux, France., Rodger MA; Department of Medicine, McGill University, Montreal, QC, Canada., Gagnon F; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.; University of Toronto Mississauga, Toronto, Canada., Rosendaal FR; Department of Clinical Epidemiology, Leiden university Medical Center, Leiden, the Netherlands., Johnson AD; Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.; The Framingham Heart Study, Boston University, Framingham, MA, USA., Smith NL; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA 98101, USA.; Department of Epidemiology, University of Washington, Seattle WA, USA.; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle WA 98108, USA., Couturaud F; Univ Brest, Inserm, UMR 1304, GETBO, Brest, France.; Chest disease unit, CHU Brest, Brest, France., Morange PE; Cardiovascular and Nutrition Research Center (C2VN), INSERM, INRAE, Aix-Marseille University, Marseille, France.; Biogenopole, Hematology Laboratory, La Timone University Hospital of Marseille, 264 Rue Saint-Pierre, Marseille, 13385, France.; Assistance Publique des Hopitaux de Marseille (APHM), Biological Resource Center - 264 Rue Saint-Pierre, Marseille, 13385, France., Trégouët DA; Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, F-33000 Bordeaux, France.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Dec 03. Date of Electronic Publication: 2024 Dec 03.
DOI:	10.1101/2024.12.02.24317788
Abstrakt:	Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding. We analysed the genomic architecture of VT recurrence using data from 6,571 patients across eight cohorts, 1,816 of whom experienced recurrence, with a particular focus on the clinical manifestation of the type of first VT event. Through genome-wide association studies (GWAS), we identified three loci significantly associated (P<5×10 -8 ) with VT recurrence in the general VT population: GPR149/MME , L3MBTL4 , and THSD7B . Protein Quantitative Trait Locus and Mendelian Randomization analyses further identified elevated plasma levels of coagulation factor XI and GOLM2 as risk factors for recurrence, while decreased levels of PCSK9 and pro-IL16 were linked to reduced VT recurrence risk. Subgroup analyses revealed 18 loci associated with VT recurrence, with notable differences between pulmonary embolism (PE) and deep vein thrombosis (DVT). For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated with recurrence in PE patients (Hazard Ratio (HR)=3.23, P=9.7×10 -12 ) but showed no effect in DVT (HR=1.00, P=0.98). These findings emphasize the role of specific genetic loci and protein pathways in influencing VT recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations. Competing Interests: Disclosures The authors have no conflict of interest to declare.
Databáze:	MEDLINE
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