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.
Highlights
Venous thrombosis (VT) is a common complex disease characterized by a sibling relative risk of,3 [1] and heritability estimates ranging from 30% to 60% [2,3]
The starting hypothesis of this work was that DNA methylation marks associate with the F5 rs6025 mutation and contribute to the incomplete penetrance of this strong genetic risk factor for VT
We undertook the first MWAS of the F5 rs6025 in a large sample of 349 individuals and replicated the findings in an independent sample of 214 related subjects
Summary
Venous thrombosis (VT) is a common complex disease characterized by a sibling relative risk of ,3 [1] and heritability estimates ranging from 30% to 60% [2,3]. The penetrance of the FV Leiden mutation (i.e. F5 R506Q or rs6025T/C), one of the major VT genetic risk factors present in about 5% of the general population, is quite low, only 10% of heterozygotes and 80% of homozygotes develop VT in their lifetime, with varying severity among affected individuals. These observations suggest that additional genetic and non-genetic factors contribute to the incomplete penetrance of FV
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