Aim: To integrate transcriptomic and DNA-methylomic measurements on varicose versus normal veins using a systems biological analysis to shed light on the interplay between genetic and epigenetic factors. Materials & methods: Differential expression and methylation were measured using microarrays, supported by real-time quantitative PCR and immunohistochemistry confirmation for relevant gene products. A systems biological 'upstream analysis' was further applied. Results: We identified several potential key players contributing to extracellular matrix remodeling in varicose veins. Specifically, our analysis suggests MFAP5 acting as a master regulator, upstream of integrins, of the cellular network affecting the varicose vein condition. Possible mechanism and pathogenic model were outlined. Conclusion: A coherent model proposed incorporates the relevant signaling networks and will hopefully aid further studies on varicose vein pathogenesis.