Genome-Wide Investigation of Exogenous Female Hormones, Genetic Variation, and Venous Thromboembolism Risk.

Oral contraceptives epidemiology gene-environment interaction hormone replacement therapy venous thromboembolism

Journal

Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508

Informations de publication

Date de publication:
21 May 2024
Historique:
received: 12 12 2023
revised: 02 04 2024
accepted: 13 05 2024
medline: 24 5 2024
pubmed: 24 5 2024
entrez: 23 5 2024
Statut: aheadofprint

Résumé

Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT). To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment (GxE) case-only meta-analysis of genome-wide association studies (GWAS). Use or non-use of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and estimated supra-multiplicative GxE interaction. The SI parameters were first meta-analyzed across OC and HT studies, and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a p-value threshold of <5.0x10 The VTE case-only OC meta-analysis included 2,895 OC users and 6,607 non-users; the case-only HT meta-analysis included 2,434 HT users and 12,793 non-users. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest p-value approached statistical significance: rs9386463 (p = 5.03x10 The candidate-variant approach to identify supra-multiplicative associations between genetic variation and OC-HT use identified a new association with common genetic variation in F11 while the agnostic interrogations did not yield new discoveries.

Sections du résumé

BACKGROUND BACKGROUND
Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT).
OBJECTIVES OBJECTIVE
To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment (GxE) case-only meta-analysis of genome-wide association studies (GWAS).
METHODS METHODS
Use or non-use of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and estimated supra-multiplicative GxE interaction. The SI parameters were first meta-analyzed across OC and HT studies, and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a p-value threshold of <5.0x10
RESULTS RESULTS
The VTE case-only OC meta-analysis included 2,895 OC users and 6,607 non-users; the case-only HT meta-analysis included 2,434 HT users and 12,793 non-users. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest p-value approached statistical significance: rs9386463 (p = 5.03x10
CONCLUSIONS CONCLUSIONS
The candidate-variant approach to identify supra-multiplicative associations between genetic variation and OC-HT use identified a new association with common genetic variation in F11 while the agnostic interrogations did not yield new discoveries.

Identifiants

DOI: 10.1016/j.jtha.2024.05.011 PMID: 38782299
pubmed: 38782299
pii: S1538-7836(24)00294-0
doi: 10.1016/j.jtha.2024.05.011
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Emily K Hasser (EK)

Epidemiology, University of Washington, Seattle, Washington, 98195, United States.

Jennifer A Brody (JA)

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States.

Traci M Bartz (TM)

Departments of Biostatistics and Medicine, University of Washington, Seattle, Washington, 98195, United States.

Florian Thibord (F)

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, 146 rue Léo Saignat, Bordeaux, 33076, France,; Laboratory of Excellence on Medical Genomics (GENMED), France.

Ruifang Li-Gao (R)

Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, Netherlands.

Anni Kauko (A)

Department of Internal Medicine, University of Turku, Kiinamyllynkatu 4-8, Turku, 20014, Finland.

Kerri L Wiggins (KL)

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States.

Maris Teder-Laving (M)

Institute of Genomics, University of Tartu, Riia 23b, Tartu, 51010, Estonia.

Jihye Kim (J)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, Massachusetts, 02115, United States.

Gaëlle Munsch (G)

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, 146 rue Léo Saignat, Bordeaux, 33076, France.

Helen G Haile (HG)

Epidemiology, University of Washington, Seattle, Washington, 98195, United States.

Jean-Francois Deleuze (JF)

Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 2 Rue Gaston Crémieux, Evry, 91057, France,; Centre D'Etude du Polymorphisme Humain, Fondation Jean Dausset, 27, rue Juliette Dodu, Paris, 75010, France,; Laboratory of Excellence on Medical Genomics (GENMED), France.

Astrid van Hylckama Vlieg (A)

Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, Netherlands.

Alisa S Wolberg (AS)

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 8018A Mary Ellen Jones Building, CB 7035, Chapel Hill, North Carolina, 27599, United States.

Anne Boland (A)

Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 2 Rue Gaston Crémieux, Evry, 91057, France,; Laboratory of Excellence on Medical Genomics (GENMED), France.

Pierre-Emmanuel Morange (PE)

Hematology Laboratory, La Timone University Hospital of Marseille, 264 Rue Saint-Pierre, Marseille, 13005, France,; Centre de recherche en CardioVasculaire et Nutrition, INSERM, INRAE, Aix-Marseille University, 264 Rue Saint-Pierre, Marseille, 13005, France.
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia.

Peter Kraft (P)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, Massachusetts, 02115, United States,; Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, Massachusetts, 02115, United States.

Charles J Lowenstein (CJ)

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, United States.

Joseph Emmerich (J)

Department of vascular medicine, Paris, Saint-Joseph Hospital Group, University of Paris Cité, 185 rue Raymond Losserand, Paris, 75674, France,; UMR1153, INSERM CRESS, 185 rue Raymond Losserand, Paris, 75674, France.

Colleen M Sitlani (CM)

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States.

Pierre Suchon (P)

Hematology Laboratory, La Timone University Hospital of Marseille, 264 Rue Saint-Pierre, Marseille, 13005, France,; Centre de recherche en CardioVasculaire et Nutrition, INSERM, INRAE, Aix-Marseille University, 264 Rue Saint-Pierre, Marseille, 13005, France.

Frits R Rosendaal (FR)

Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, Netherlands.

Teemu Niiranen (T)

Department of Internal Medicine, University of Turku, Kiinamyllynkatu 4-8, Turku, 20014, Finland,; Division of Medicine, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, 20014, Finland,; Department of Public Health Solutions, Finish Institute of Health and Welfare, P.O. Box 30, Helsinki, 00271, Finland.

Christopher Kabrhel (C)

Department of Emergency Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, United States,; Department of Emergency Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts, 02115, United States.

David-Alexandre Trégouët (DA)

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, 146 rue Léo Saignat, Bordeaux, 33076, France,; Laboratory of Excellence on Medical Genomics, France.

Nicholas L Smith (NL)

Epidemiology, University of Washington, Seattle, Washington, 98195, United States,; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, Washington, 98101, USA,; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington, 98108, USA. Electronic address: nlsmith@u.washington.edu.

Classifications MeSH