Sex-Specific Gene Expression Differences in Varicose Veins

Background/Objectives: There is clear evidence for the higher prevalence of varicose veins (VVs) among women. In this regard, the research on sex differences affecting this condition is very important for sex-specific health care. We aimed to assess how male or female sex may contribute to the changes to gene expression profiles in the vein wall during varicose transformation. Methods: Paired varicose vein (VV) and non-varicose vein (NV) segments were harvested from patients with VVs after venous surgery. Processed RNAs from those samples were subjected to gene expression analysis by reverse transcription quantitative polymerase chain reaction (RT-qPCR) followed by further data analysis. Multiple linear regression (MLR) analysis was performed to identify and characterize relationships among multiple factors (relative mRNA levels of a gene in NV or VV or their ratio, as dependent variables) and sex (independent variable, used individually or in combination with other patient's characteristics). For sex-specific gene regulation analysis, all potential binding sites for sex hormone receptors were identified in each gene's regulatory region sequence. Results: Using the independent method and a replicative patient sample set, we validated our previous data on 23 genes' differential expression in VVs and obtained insights on their sex-specific regulation. Sex (as an individual independent variable or in combination with other parameters-patient characteristics such as Age, BMI, CEAP class, Height, VVD manifestation and duration) was a moderate predictor (0.40 < R < 0.59; p (R) < 0.05) for the STK38L expression in VVs (with its higher mRNA level in NVs and VVs of women compared to men); sex was a strong predictor (0.6 < R < 0.79; p (R) < 0.05) for the TIMP1 expression in VVs (with its lower mRNA level in VVs of women compared to men); sex was a moderate predictor (0.40 < R < 0.59; p (R) < 0.05) for the EBF1 expression in NVs (with its lower mRNA level in NVs of women compared to men). Conclusions: Confirmed differential expression of the studied genes in VVs indicates their plausible participation in vein wall remodeling. Sex-specific expression in veins for the subset of those genes suggests their hormonal regulation as well as other mechanisms involved in VV pathogenesis. This work enriches our understanding of sex features for the development of VVs and may provide the foundation for future investigations and beneficial treatment options.