OC 17.2 - New insights on the genetics of venous thromboembolism recurrence from a GWAS analysis of 6,504 patients including 1,797 recurrent events

Sunday, June 25, 2023

11:00 – 11:15 ET

Room: 524

Session Available As: On-Demand

Presenting Author(s)

Gaëlle Munsch, PhD

Post-Doctoral Researcher
Inserm U1219 Bordeaux Population Health Research Center, University of Bordeaux
Bordeaux, Aquitaine, France

Co-Author(s)

JB

Jennifer A. Brody

Research Scientist
Department of Medicine, University of Washington, Seattle WA, USA.
Seattle, Washington, United States
Astrid van Hylckama Vlieg, PhD

Associate Professor
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
Florian Thibord, PhD

Post-Doctoral Fellow
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.
Jamaica Plain, Massachusetts, United States
FG

France Gagnon

Professor
Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
Toronto, Ontario, Canada
LG

Lénaïck Gourhant

Research Assistant
Department of internal medicine and chest diseases, INSERM U1304_GETBO, Univ_Brest, CHU_Brest, Brest, France
Brest, Bretagne, France
LG

Louisa Goumidi

Research Scientist
Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, CRB Assistance Publique – Hôpitaux de Marseille, HemoVasc (CRB AP-HM HemoVasc), Marseille, France.
Marseille, Provence-Alpes-Cote d'Azur, France
MG

Marine Germain

INSERM Research Assistant
University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR1219, Bordeaux, France.
Bordeaux, Aquitaine, France
AB

Anne Boland

Team Leader
Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
Evry, Ile-de-France, France
JD

Jean-François Deleuze

Director
Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
Paris, Ile-de-France, France
HJ

Hélène Jacqmin-Gadda

INSERM Research Director
University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR1219, Bordeaux, France.
Bordeaux, Aquitaine, France
NS

Nicholas L. Smith

Professor, Epidemiology
Department of Epidemiology, School of Public Health, University of Washington
Seattle, Washington, United States
FR

Frits R. R. Rosendaal

Professor
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
Andrew D. D. Johnson, PhD (he/him/his)

Professor
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.
Framingham, Massachusetts, United States
Marc A. Rodger, MD (he/him/his)

Professor
Department of Medicine, McGill University, McGill University Health Center, Montreal, Quebec, Canada
Montreal, Quebec, Canada
Francis Couturaud, PhD (he/him/his)

MD, PhD
Centre Hospitalo-Universitaire de Brest, Département de Médecine Interne et Pneumologie, INSERM U1304, CIC INSERM 1412, Univ_Brest, Brest, FCRIN INNOVTE, France.
Brest, Bretagne, France
PM

Pierre-Emmanuel Morange, MD, PhD

MD, PhD
Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, Hôpitaux de Marseille, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
David-Alexandre TREGOUET, PhD (he/him/his)

Senior Investigator
Bordeaux Population Health research center - INSERM UMR1219
Bordeaux, Aquitaine, France

Background: Venous thromboembolism (VTE) is a frequent (annual incidence of 1 to 2 per 1,000) 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 of ~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. There is urgent need to identify risk factors for recurrence in order to optimize modalities and duration of anticoagulant treatment.

Aims: To identify novel genetic factors associated with VTE recurrence.

Methods: Genome-wide association studies (GWAS) for VTE recurrence were conducted in six international VTE cohorts followed up for recurrence (Table 1) and totalling 6,540 VTE patients among which 1,797 developed a recurrent event during the follow-up. Association results at 7,298,042 single nucleotide polymorphisms were then meta-analyzed using a fixed effect method.

Results: Two loci reached genome-wide significance (p < 5x10-8) (Figure 1). On chromosome 2q22.1, nearby THSD7B, the rs72844599-T allele was associated with VTE recurrence: hazard ratio (HR) 2.03 [1.32-3.12] (p=6.10x10-9). The second signal was observed at rs73149254, mapping to the GATA5 3’UTR on chromosome 20q13.33, where the rare A allele was associated with VTE recurrence: HR 1.81 [1.27-2.58] (p=4.28x10-8). Associations were homogeneous across cohorts (I2=0.23, I2=0, respectively, p>0.10 for both). THSD7B encodes the thrombospondin glycoprotein involved in angiogenesis and has been previously suggested to associate with pediatric VTE. GATA5 is also known to participate to angiogenesis but also to endothelial cells function.

Conclusion(s): Our analyses identified two novel genetic factors for VTE recurrence. Ongoing downstream analyses, including transcriptome-/proteome-wide association studies, Mendelian Randomization and rare variant analyses, will add new knowledge on the genetic architecture underlying VTE recurrence and possible new therapies.

Learning Objectives:

Upon completion, participant will have an overview of the genetic factors for VTE recurrence.
Upon completion, participant will be able to understand the basic concepts to conduct GWAS meta-analysis.
Upon completion, participant will be able to demonstrate the necessity to indentify genetic risk factors for VTE recurrence