The Causal Relationship Between Multiple Modifiable Risk Factors and Hallux Valgus: A Two-Sample Mendelian Randomization Study

Abstract

This Mendelian randomization (MR) study aimed to investigate the potential causal associations between modifiable lifestyle/metabolic factors and the risk of hallux valgus (HV), a common foot deformity characterized by lateral deviation of the great toe. We selected independent genetic variants strongly associated with five lifestyle factors (lifetime smoking index, smoking initiation, alcohol consumption, coffee intake, and vigorous physical activity) and ten metabolic traits (body mass index (BMI), waist-hip ratio, type 2 diabetes, systolic/diastolic blood pressure, high/low-density lipoprotein, apolipoprotein A-1/B, and triglycerides) as instrumental variables through rigorous quality control (R² < 0.001, p ≤ 5 × 10⁻⁸). Genetic association estimates were derived from large-scale genome-wide association studies (GWAS) in the UK Biobank, GSCAN consortium, and FinnGen cohorts. A two-sample MR approach was used to assess causal effects on HV risk. Genetically predicted smoking initiation (odds ratio (OR) 1.23, 95% confidence interval (CI) [1.06–1.43], p = 0.00784), lifetime smoking (OR 1.79, 95% CI [1.27–2.51] p = 0.000832), and higher BMI (OR 1.17, 95% CI [1.06–1.29] p = 0.00164) were significantly associated with increased HV risk. No significant associations were found for other tested factors. This study provides genetic evidence supporting a causal role of smoking and BMI in the development of HV. These findings highlight modifiable risk factors for targeted prevention strategies in HV management.