Glucose Levels and Granulocyte Colony-Stimulating Factor May Partially Mediate the Association Between Genetic Liability to Diabetes and Carpal Tunnel Syndrome

BACKGROUND: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy, imposing substantial clinical and socioeconomic burdens due to chronic pain, functional disability, and reduced quality of life. While diabetes is a well-established risk factor for CTS in observational studies, the causal nature of this association and the mediating roles of glucose levels and inflammatory pathways remain unclear. METHODS: We conducted a two-sample Mendelian randomization study using genetic data primarily from the UK Biobank. We assessed the causal effect of genetic liability to diabetes on CTS and evaluated genetically predicted glucose levels, HbA1c, and circulating levels of 41 inflammatory cytokines as potential mediators. Complementary analyses examined other genetically proxied CTS risk factors, including BMI and genetic liability to osteoarthritis. The inverse-variance weighted method was primary, supported by sensitivity analyses. RESULTS: Genetic liability to diabetes was significantly associated with increased CTS risk (IVW OR: 3.36, 95% CI: 1.46 - 7.74, P = 0.0045). Mediation analysis indicated that genetically predicted higher glucose levels levels partially mediated this relationship (IVW OR: 1.28, 95% CI: 1.08 - 1.53, P = 0.0048), whereas genetically predicted HbA1c levels showed no significant association. Among inflammatory markers, genetically predicted circulating granulocyte colony-stimulating factor (G-CSF) levels emerged as a potential mediator (IVW OR: 1.05, 95% CI: 1.01 - 1.10, P = 0.018). Genetic liability to higher BMI, osteoarthritis, smoking status, hypothyroidism, and sleep apnoea syndrome was also significantly associated with increased CTS risk, while genetically predicted higher sex hormone-binding globulin (SHBG) levels were inversely associated with CTS. Sensitivity analyses revealed no evidence of directional pleiotropy or heterogeneity. CONCLUSION: This study provides genetic evidence supporting a causal effect of genetic liability to diabetes on CTS. The association may be partly mediated by genetically predicted glucose levels and candidate inflammatory pathways involving G-CSF, although these mediation findings require further validation.