Molecular Genetics of Primary Varicose Vein Disease

Abstract

There is sufficient empirical evidence to suggest that there is a significant genetic contribution to the development of varicose vein (VV) disease. However, it is also clear that VV is a complex disease, which is ultimately determined by a number of genetic and environmental factors. The fact that VV are also a secondary manifestation of other vascular conditions further convolutes the understanding of the aetiology and the underlying molecular mechanisms. Despite there being many techniques which are routinely used to characterise the genetic factors involved, these strategies have inherent limitations. Furthermore, the elucidation of a factor's contribution is a complex process, due to the fact that any effect present may be confounded by other parallel effects. To fully understand the genetic contribution to VV disease, there is a need to formulate a rigorous research protocol which should utilise some of the very advanced genetic approaches. Key Concepts: Family history, age, sex and pregnancy are the established risk factors for varicose vein disease; however, not all individuals with these risk factors develop the disease. Abnormal changes in varicose vein walls have been noticed independent of valve damage suggesting that primary vein wall damage is an epiphenomenon of the disease. However, the molecular mechanism behind the vein wall damage is poorly understood. Empirical evidence suggests a strong genetic link to the disease; however, questionnaire‐based studies are subject to biases. There are several approaches available to determine the genetic link. Genes expression profiling using microarray technique has been used in varicose veins but it does not explain whether the expressed genes are the cause or the effect of the disease. Candidate gene studies have shown that FOXC2, desmuslin, thrombomodulin and methylenetetrahydrofolate reductase have been found to be associated with varicose veins. Candidate gene approach requires a very detailed knowledge of the disease biology which unfortunately does not exist for varicose veins. Synchronised use of technologies including genome‐wide association study (GWAS), metabonomics and micro‐RNA analysis have the potential to elucidate the molecular mechanism of the disease and identify the underlying genetic association.