The causal relationship between hallux valgus and endogenous pathogenic factors: A 2-sample Mendelian randomization

Notably, several factors are associated with hallux valgus (HV); however, their causal relationship remains unclear. In this study, a 2-sample Mendelian randomization (MR) analysis was performed to investigate the casual relationship between 9 endogenous risk factors and HV, aiming to provide a foundation for the clinical management of HV. Exposure factors such as body mass index (BMI), BMI (male), BMI (female), acquired flatfoot, rheumatoid arthritis, gout, knee osteoarthritis, hip osteoarthritis, and Ehlers-Danlos syndrome were considered, with HV as the outcome. Exposure and outcome data were obtained from the IEU Open Genome-wide association study project, UK Biobank, and FinnGen project. Strongly correlated (P < 5x10-08/5x10-06) single nucleotide polymorphisms (SNPs) were selected from the exposure dataset, and those associated with exposure were selected from the HV dataset. The intersection of these SNPs was used as instrumental variables. Five modes were used for the analysis: inverse variance-weighted (IVW), MR-Egger regression, weighted median (WME), simple mode, and weighted mode. MR analysis results of BMI show that except for MR-Egger, the other 4 modes are significant (P < .05), and the beta directions are consistent among the 5 methods. For the 4 BMI (male) methods, except for the simple mode, the P- and beta-values of the other results all suggest a positive causal relationship between BMI (male) and HV. Flatfoot-IVW and WME results were <.05, indicating statistical significance, whereas MR-Egger, simple mode, and median mode had no statistical significance. However, their beta-values were consistent with those of IVW and WME. Further mediation MR analysis suggested that the effect mediated by HV accounts for 13.33% [95% CI (0.03-0.24)] of the total causal effect between the BMI and flatfoot, indicating HV as a mediator of the causal relationship between the BMI and flatfoot. However, the remaining 6 factors had no direct causal association with HV (P < .05). Flatfoot in all patients and elevated BMI in males are directly associated with HV. Therefore, treating acquired flatfoot and controlling the BMI to prevent HV are recommended.