Progression in chronic venous disease (CVD) may be determined by behavioural, environmental or clinical factors rather than genetic ones, according to new research presented at the 26th annual meeting of the European Venous Forum (EVF; 25–27 June, Versailles, France). The paper, presented by Jessica Bowie (Imperial College London, London, UK), won third prize for best presentation at the meeting.
Bowie began by explaining that CVD presents as a spectrum of skin change, with heterogenous presentation and rates of progression seen between patients.
The presenter noted that there has been little research to date exploring potential genetic factors behind the progression of CVD and development of venous leg ulceration (VLU). As a result, Bowie and colleagues at Imperial College London, including senior author Alun Davies, aimed to establish possible genetic drivers of CVD progression using data from the UK Biobank cohort.
To explore this under-researched area, the investigators performed genome-wide association studies (GWAS) using the REGENIE modelling programme (version 2.1.1) on UK Biobank participants of European ancestry.
Bowie shared that phenotype was defined using self-reported data, hospital admission codes and general practice records. Three mutually exclusive hierarchical phenotypes were constructed based on the clinical stage of the CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classification, corresponding to C2 (varicose veins), C4 (varicose veins with skin change) and C6 (varicose veins with active VLU).
The team’s analysis after quality control included 15,519 C2 (3.8%), 1,102 C4 (0.27%), and 663 C6 (0.16%) patients, with 390,318 controls.
Bowie revealed at EVF 2026 that, comparing controls to C2 patients, GWAS identified 2,694 genome-wide significant single nucleotide polymorphisms (SNPs) across 15 chromosomes. These mapped to 45 independent loci, including established genes linked to venous disease such as CASZ1 and RNF166, and new loci such as TMBIM6 and FBN2.
The team’s quantile-quantile (QQ) plot demonstrated clear deviation consistent with a strong polygenic signal (λGC=1.17), Bowie added. Contrastingly, between controls, C4 and C6 patients, and between C2 and C4, C4 and C6 and C2 and C6, only very rare variant associations were found, which did not survive linkage disequilibrium (LD) clumping, and QQ plots closely following the null expectation (λGC≈1.00–1.05).
“This project is the first to explore potential genetic variants associated with VLU and skin change in CVD,” Bowie said in her concluding remarks. “While the development of varicose veins has a strong polygenic basis, there was no genetic signal present to distinguish patients with C6 disease. This absence of reproducible genetic risk suggests that progression in CVD is determined by modifiable behavioural, environmental or clinical factors, rather than inherited ones; however, small samples of C4 and C6 may have introduced type 1 error.”
Bowie continued that new genetic loci identified are associated with cardiovascular risk (TMBIM6) and connective tissue disorders (FBN2), highlighting potential shared underlying genetic architecture.
“These findings support the notion of increased cardiovascular risk in patients with CVD, and the need to identify environmental drivers of CVD progression,” the presenter stated.
Speaking to Venous News following her presentation, Bowie remarked on the significance of the study and its findings: “Access to biobank datasets allows us to explore the genetics of chronic venous disease in ways that haven’t been possible before. By stratifying patients by CEAP stage, we were able to uncover new genetic loci associated with varicose veins and highlight the fact that progression to C4 and C6 disease may be due to epigenetic and environmental factors instead of inherited genetic risk.”
