Causal effects of type 2 diabetes, obesity, gout, and hypothyroidism on carpal tunnel syndrome: a univariable and multivariable Mendelian randomization study

Background: Carpal tunnel syndrome (CTS) is a prevalent peripheral neuropathy with unclear pathogenesis. This study investigated the causal relationships between metabolic diseases and CTS using univariable and multivariable Mendelian randomization (MR) analyses. Methods: Single nucleotide polymorphisms from large genetic databases served as instrumental variables. Genome-wide data on type 2 diabetes (T2D), obesity, gout, hypothyroidism, and CTS were obtained from the IEU OpenGWAS Project (Integrative Epidemiology Unit Open Genome-Wide Association Studies Project). Univariable MR analysis assessed individual causal effects, and multivariable MR evaluated combined effects. Sensitivity analyses examined heterogeneity and pleiotropy. Results: The univariable MR analysis identified significant associations of CTS with obesity (odds ratio [OR], 1.0135; 95% confidence interval [CI], 1.0118-1.0151; P<0.001), T2D (OR, 1.0028; 95% CI, 1.0011-1.0045; P=0.0011), gout (OR, 1.0559; 95% CI, 1.0152-1.0982; P=0.0067), and hypothyroidism (OR, 1.0517; 95% CI, 1.013-1.0919; P=0.0084). The multivariable MR analysis confirmed obesity (OR, 1.0129; 95% CI, 1.0088-1.0171; P<0.001) and T2D (OR, 1.002; 95% CI, 1.0006-1.0033; P=0.0042) as significant independent risk factors. Gout and hypothyroidism lost significance after adjustment. No notable pleiotropy was observed. Conclusion: Obesity and T2D independently increase CTS risk, whereas the univariable associations for gout and hypothyroidism were attenuated after adjustment for other metabolic conditions, suggesting mediation by or confounding with obesity and glucose metabolism in this dataset.