title: Genome-wide investigation of DNA methylation marks associated with FV Leiden mutation.
abstract: In order to investigate whether DNA methylation marks could contribute to the incomplete penetrance of the FV Leiden mutation, a major genetic risk factor for venous thrombosis (VT), we measured genome-wide DNA methylation levels in peripheral blood samples of 98 VT patients carrying the mutation and 251 VT patients without the mutation using the dedicated Illumina HumanMethylation450 array. The genome-wide analysis of 388,120 CpG probes identified three sites mapping to the SLC19A2 locus whose DNA methylation levels differed significantly (p<3 10-8) between carriers and non-carriers. The three sites replicated (p<2 10-7) in an independent sample of 214 individuals from five large families ascertained on VT and FV Leiden mutation among which 53 were carriers and 161 were non-carriers of the mutation. In both studies, these three CpG sites were also associated (2.33 10-11<p<3.02 10-4) with biomarkers of the Protein C pathway known to be influenced by the FV Leiden mutation. A comprehensive linkage disequilibrium (LD) analysis of the whole locus revealed that the original associations were due to LD between the FV Leiden mutation and a block of single nucleotide polymorphisms (SNP) located in SLC19A2. After adjusting for this block of SNPs, the FV Leiden mutation was no longer associated with any CpG site (p>0.05). In conclusion, our work clearly illustrates some promises and pitfalls of DNA methylation investigations on peripheral blood DNA in large epidemiological cohorts. DNA methylation levels at SLC19A2 are influenced by SNPs in LD with FV Leiden, but these DNA methylation marks do not explain the incomplete penetrance of the FV Leiden mutation.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Dylan
authors.initials: D
authors.lastname: Aïssi
authors.affiliation: Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dennis
authors.affiliation: Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; Centre de Recherches du CHUM, Montréal, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Ladouceur
authors.affiliation: Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
authors.forename: Vinh
authors.initials: V
authors.lastname: Truong
authors.affiliation: Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
authors.forename: Nora
authors.initials: N
authors.lastname: Zwingerman
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Ares
authors.initials: A
authors.lastname: Rocanin-Arjo
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Germain
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Tara A
authors.initials: TA
authors.lastname: Paton
authors.affiliation: Aix-Marseille University, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille, France; INSERM, UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille, France; Laboratory of Haematology, La Timone Hospital, Marseille, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Morange
authors.affiliation: Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
authors.forename: France
authors.initials: F
authors.lastname: Gagnon
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France; ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
mesh_terms: D000328:Adult; D019175:DNA Methylation; D005165:Factor V / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: C095381:factor V Leiden; D005165:Factor V