Interestingly, this polyubiquitin-dependent scaffolding appears to be dispensable when several RIG-I molecules are associated with one long RNA in agreement with RIG-I CARD tandem forming complexes with MAVS CARD. Several lines of evidence support the role of DNA methylation marks as contributing factors in complex human diseases, including thrombosis-related disorders. For example, quantitative risk factors for VT such as body-mass-index and levels of von Willebrand factor, Factor VIII, and homocysteine have been associated with DNA methylation marks. Further, lifestyle and environmental VT risk factors, such as smoking and air pollution, have been associated with methylation levels in genes relevant to VT pathophysiological mechanisms. Until recently, such investigations were restricted to experimental models or small study samples, and restricted to candidate genomic regions. The recent enthusiasm for agnostic investigations of methylation marks in peripheral blood DNA as a mean to investigate complex disease etiology and to generate novel mechanistic hypotheses is justified. First,genome-wide methylation arrays, such as the Illumina HumanMethylation450 bead array, are now widely recognized as robust and efficient tools for epidemiological studies aiming at identifying methylation marks at CpG sites associated with environmental and genetic risk factors. Second, biobanked peripheral blood DNA has been shown to be a robust and practical model for epidemiological epigenetic investigations. Third, evidence of peripheral blood DNA methylation marks as surrogates for methylation marks at other disease relevant tissues and cell types are increasingly emerging. As whole blood DNA methylation levels reflect the average level resulting from the epigenetic state at different cell types, the identification of DNA methylation marks in peripheral blood cells may point out to novel biological mechanisms that subsequently can be validated in the principal effector cell types where stronger associations are expected. Finally, and specific to this study, DNA from peripheral blood originates mainly from leukocytes, which are key effector cells for both coagulation and inflammation, the two principal pathophysiological mechanisms underlying VT. 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. Thus, we undertook the first MWAS of the F5 rs6025 in a large BAY-60-7550 sample of 349 individuals and replicated the findings in an independent sample of 214 related subjects. We identified and replicated three CpG sites exhibiting a genome-wide significant difference in methylation levels in carriers and non-carriers of the mutation. These CpG sites were also strongly associated with the plasma variability of quantitative biomarkers influenced by the F5 rs6025. However, when we integrated our MWAS and GWAS data, the observed associations between methylation levels at three CpG sites in SLC19A2 and F5 rs6025 were in fact due to LD between the rs6025 and SNPs located in SLC19A2.