Background:Varicose veins are found to be associated with increased risk of venous thromboembolism (VTE) in many observational studies, but whether varicose veins are causally associated with VTE remains unclear. Therefore, we used a series of Mendelian randomization (MR) methods to investigate that association.Methods23 independent single-nucleotide polymorphisms (SNPs) for varicose veins were obtained from the Pan UK Biobank analysis. The outcomes datasets for deep vein thrombosis (DVT), pulmonary embolism (PE) and venous thromboembolism (VTE) were obtained from the FinnGen study. Before analysis, body mass index (BMI) and height were included as confounders in our MR model. Basic MR [inverse-variance weighted (IVW), weight-median, penalized weighted-median and MR-Egger methods] and MR-PRESSO were performed against each outcome using the whole SNPs and SNPs after excluding those associated with confounders. If causal associations were suggested for any outcome, a basic MR validation analysis, a multivariable MR analysis with BMI and height, a Causal Analysis Using Summary Effect estimates (CAUSE), and a two-step MR analysis with BMI and height, would follow.ResultsUsing 21 qualified SNPs, the IVW method (OR: 1.173, 95% CI: 1.070–1.286, p < 0.001, FDR = 0.002), the weighted median method (OR: 1.255, 95% CI: 1.106–1.423, p < 0.001, FDR = 0.001), the penalized weighted median method (OR: 1.299, 95% CI: 1.128–1.495, p < 0.001, FDR = 0.001) and the MR-PRESSO (OR: 1.165, 95% CI: 1.067–1.273, p = 0.003, FDR = 0.009) suggested potential causal effect of varicose veins on DVT, but no cause effect was found for PE and VTE. Excluding SNPs associated with confounders yielded similar results. The causal association with DVT was validated using a self-reported DVT cohort (IVW, OR: 1.107, 95% CI: 1.041–1.178, p = 0.001). The causal association maintained after adjustment for height (OR = 1.105, 95% CI: 1.028–1.188, p = 0.007), BMI (OR = 1.148, 95% CI: 1.059–1.244, p < 0.001) and them both (OR = 1.104, 95% CI: 1.035–1.177, p = 0.003). The causal association also survived the strict CAUSE (p = 0.018). Finally, in two-step MR, height and BMI were found to have causal effects on both varicose veins and DVT.ConclusionGenetically predicted varicose veins may have a causal effect on DVT and may be one of the mediators of obesity and taller height that predispose to DVT.

Objective: The effect of Zinc Finger Protein-Activating Transcription Factor ( ZFP-ATF) stimulating the angiogenesis and maturity of neovascularization with the overexpression of the vascular endothelial growth factor(VEGF )were investigated in a mouse ischemia hindlimb model and rat mesenteric assay；Methods: After the synthesis of ZFP-ATP, the ischemic hindlimb mice were successfully constructed. ZFP-ATF, VEGF165 and saline control were injected into the ischemic muscles, respectively. After 14 days, the number of mice with different ischemic degree was counted, moreover,the ischemic gastrocnemius and soleus muscle were harvested for the immunohistochemical staining and VEGF protein analysis.Besides, in the rat mesenteric assay, ZFP-ATF, VEGF165 and saline control were injected into mesenteric adipose tissues, respectively. After 14 days, the number of neovessels in different groups was calculated. Meanwhile, mesenteric immunofluorescence staining was performed to evaluate the pericyte coverage.Results: In the mouse with the ischemic hindlimb, the expression of VEGF protein in the ZFP-ATF group was significantly higher,at the same time, the number of neovessels in the ZFP-ATF evaluated by CD31 staining was significantly increased than that in the VEGF165 and blank control group. Besides, in the rat mesenteric assay, the number of neovessels in the ZFP-ATF group was dramatically increased compared with VEGF165 and blank group. In mesenteric immunofluorescence staining, the ZFP-ATF group had a more complete and successive pericytes coverage. Conclusion: ZFP-ATF stimulating the endogenous physiological angiogenesis can promote the more mature neovascularization with the complete pericyte coverage.