OC 17.5 - Genetic association of the 4q34.1 locus with residual vascular obstruction in patients with pulmonary embolism

Sunday, June 25, 2023

11:45 – 12:00 ET

Room: 524

Session Available As: On-Demand

Presenting Author(s)

Floriane Samaria (she/her/hers)

Master Student
Bordeaux Population Health research center - INSERM UMR1219
Bordeaux, Aquitaine, France

Co-Author(s)

Gaëlle Munsch, PhD

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

Lénaïck Gourhant

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

Catherine A. Lemarie, PhD

INSERM researcher
Department of internal medicine and chest diseases, INSERM U1304_GETBO, Univ_Brest, CHU_Brest, Brest, France
Brest, Bretagne, 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)
Evry, Ile-de-France, France
JD

Jean-François Deleuze

Director
Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)
Evry, Ile-de-France, France
David-Alexandre TREGOUET, PhD (he/him/his)

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

Background: Pulmonary Embolism (PE) is a frequent and potentially life-threatening disease. After 3 to 6 months of anticoagulant therapy, at least 30% of patients will have developed chronic and irreversible residual pulmonary vascular obstruction (RPVO) due to incomplete thrombus resolution, which is associated with an increased risk of recurrent venous thromboembolism, impaired quality of life and can be associated with pulmonary hypertension.

Aims: To identify genetic determinants of RPVO in PE patients

Methods: A genome-wide association studies (GWAS) for the presence of RPVO was conducted in 381 PE patients from the EDITH cohort. RPVO was measured with ventilation perfusion lung scintigraphy and was defined as a PVO index >5%. About 8 million imputed single nucleotide polymorphisms (SNPs) were tested for association with RPVO in a case-control frameworks (193 RPVO PE patients vs 188 non-RPVO PE patients). SNPs that reached the statistical threshold of p=5x10-8 were tested for replication in the PADIS-PE randomized trial composed of 127 cases and 181 controls.

Results: One locus was significantly (p=3.5x10-8) associated with RPVO on chromosome 4q34.1 (Figure 1). Fine mapping analysis suggested that this association might be explained by the dominant effect of the rs11732436-A allele, with minor allele frequency ~0.38, that was associated with an increased odds ratio (OR) for RPVO of OR=4.31 [2.64-7.18] p=9.7x10-9. This association replicated in PADIS-PE where carrying the rs11732436-A allele was associated with an age- and sex- adjusted OR for RPVO of 1.73 [1.02–2.94] (p = 0.043).
While rs11732436 maps to MIR4276, it has also been reported to be an eQTL for nearby CEP44 and HPGD, the latter recently reported to associate with pulmonary fibrosis.

Conclusion(s): Our study, the first GWAS on RVPO, identified a novel locus associated with RVPO. Genome-wide genotyping of PADIS-PE is ongoing and results will be meta-analyzed with EDITH to identify additional genetic factors.

Learning Objectives:

Upon completion, participant will be able to compare the impact of choosing different threshold when studying residual pulmonary vascular obstruction after a first episode of pulmonary embolism.
Upon completion, participant will be able to apply a new method for semi-continuous data, such as the residual pulmonary vascular obstruction.
Upon completion, participant will be able to evaluate and judge a new biological candidate in the study of genetics risk factors of residual pulmonary vascular obstruction after a first episode of pulmonary embolism.