Venous leg ulcers (VLU), the most severe manifestation of chronic venous disease, are debilitating wounds that can remain unhealed for several decades and recur in up to 70% of cases. The progression and recalcitrance of the condition is not well understood and, although there is evidence to suggest a genetic predisposition, the genes involved have yet to be elucidated.
The HFE gene encodes for a cell surface protein which helps to regulate the absorption of dietary iron and its release from storage sites in the body. Two single nucleotide polymorphisms (SNPs) within this gene, p.C282Y and p.H63D, are directly involved in the dysregulation of iron homeostasis, leading to iron overload in various tissues and in some cases, hereditary haemachromatosis. Iron overload in the dermis has been associated with fibrosis and chronic inflammation. We hypothesise that, in combination with chronic venous insufficiency and venous stasis, these mutations in the HFE gene can predispose patients to poorer healing outcomes.
These SNPs were analysed in VLU patients and age matched controls while the protein in patient wound fluid samples was analysed using a SWATH proteomics approach. We found that 17% of the patient cohort (n = 52) had at least one HFE p.C282Y mutant allele, compared to 8% in the control cohort (n = 62). A Pearson’s Chi-squared test showed the frequencies of the p.C282Y mutant alleles to be significantly different between the two cohorts (p = 0.04).
Correlation of genotype data with the proteomic data, with particular emphasis on proteins related to iron metabolism and tissue integrity, is ongoing. It is anticipated that proteins associated with the HFE gene will have an altered abundance in non-healing or slow healing wounds.