Genome-Wide Investigation of DNA Methylation Marks Associated with FV Leiden Mutation

Dylan Aïssi (1) , Jessica Dennis (2) , Martin Ladouceur (3, 2) , Vinh Truong (2) , Nora Zwingerman (2) , Ares Rocanin-Arjo (1) , Marine Germain (1) , Tara A. Paton (4) , Pierre-Emmanuel Morange (5, 6) , France Gagnon (2) , David-Alexandre Trégouët (1)

1 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
2 University of Toronto
3 CHUM - Centre Hospitalier de l'Université de Montréal
4 SickKids - The Hospital for sick children [Toronto]
5 NORT - Nutrition, obésité et risque thrombotique
6 Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM]

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 28) between carriers and non-carriers. The three sites replicated (p,2 10 27) 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 10 211 ,p,3.02 10 24) 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.

Domaines: Médecine humaine et pathologie

Dylan Aïssi, Jessica Dennis, Martin Ladouceur, Vinh Truong, Nora Zwingerman, et al.. Genome-Wide Investigation of DNA Methylation Marks Associated with FV Leiden Mutation. PLoS ONE, 2014, 9 (9), pp.e108087. ⟨10.1371/journal.pone.0108087⟩. ⟨hal-01344494⟩