OC 36.1 - The CLEC4M locus participates to the regulation of FV plasma levels: insights from a new genome-wide association study conducted in 4,373 participants

Monday, July 11, 2022

10:45 AM – 11:00 AM

Location: ExCel Center, ICC Capital Suite Room 10&11

Presentation Format: In-Person

Presenting Author(s)

David-Alexandre TREGOUET, PhD

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

Co-Author(s)

AM

Angel Martinez-Perez

Research Associate
Genomics of Complex Diseases Group, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau
Barcelona, Catalonia, Spain
MK

Marcus Kleber

Research Associate
Department of Medicine, University Heidelberg, Mannheim Medical Faculty
Mannheim, Baden-Wurttemberg, Germany
Av

Astrid van Hylckama Vlieg, PhD

Assistant Professor
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
MG

Marine Germain

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

Jean-François Deleuze

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

Juan Carlos Souto

Doctor
Thrombosis and Haemostasis Unit, Hospital de la Santa Creu i Sant Pau and Intitut d’Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.
Barcelona, Catalonia, Spain
NS

Nicholas L. Smith

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

Maria Sabater-Lleal

Research Scientist
Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
Barcelona, Catalonia, Spain
GD

Graciela Delgado

Professor
V Medicine Clinic, University of Heidelberg
Mannheim, Baden-Wurttemberg, Germany
FR

Frits R. R. Rosendaal

Professor
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
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

Background: Factor V (FV) is a key molecular player in the coagulation cascade. FV plasma levels have been associated with several human diseases, including thrombosis, bleeding and diabetic complications. Two genes have been robustly found to contribute in the inter-individual variability of plasma FV levels: structural F5 gene and PLXDC2, a gene that has been recently identified in a genome wide association study (GWAS) conducted in 510 individuals.

Aims: To identify new genetic factors that influence the variability of FV plasma levels

Methods: A meta-analysis of 5 independent GWAS totaling 4,373 participants of European ancestry was conducted using the inverse-variance methodology

Results: Three loci reached the genome-wide significance level of 5 x 10-8 including the two already known loci: F5 with lead variant rs6027 (β = -0.151±0.008; p= 1.97 10-76 ) and PLXDC2 with lead variant rs927826 (β = -0.056±0.005; p=2.36 10-31). One novel locus was detected, CLEC4M, with lead variant rs594793 (β = -0.025±0.004; p= 2.22 10-8) whose association with FV plasma levels replicated in an independent sample of 1,019 individuals (β = -0.022±0.009; p= 0.022). Conditional analysis did not reveal any additional genome-wide significant signal at the CLEC4M locus. Interestingly, the association of rs594793 with FV plasma levels was unaltered after adjusting for plasma levels of von Willebrand factor (VWF), which have also been found to be influenced by genetic variants at CLEC4M. Consistently, the two CLEC4M polymorphisms, rs571497 and rs2277998, which have been associated with VWF plasma levels were in modest linkage disequilibrium with the rs594793 (r2 = 0.14 and r2 = 0.49) and did not exhibit a strong association with FV plasma levels (p= 6.2 10-4 and p= 1.9 10-3)

Conclusion(s): This work identifies CLEC4M as a novel locus contributing to the regulation of FV plasma levels through VWF-independent mechanisms, and this locus deserves to be more fully explored