Causal relationships between type 2 diabetes, glycemic traits and keratoconus

PURPOSE: The relationship between diabetes mellitus and keratoconus remains controversial. This study aimed to assess the potential causal relationships among type 2 diabetes, glycemic traits, and the risk of keratoconus. METHODS: We used a two-sample Mendelian randomization (MR) design based on genome-wide association summary statistics. Fasting glucose, proinsulin levels, adiponectin, hemoglobin A1c (HbA1c) and type 2 diabetes with and without body mass index (BMI) adjustment were used as exposures and keratoconus was used as the outcome. MR analysis was performed using the inverse-variance weighted method, MR-Egger regression method, weighted-mode method, weighted median method and the MR-pleiotropy residual sum and outlier test (PRESSO). RESULTS: Results showed that genetically predicted lower fasting glucose were significantly associated with a higher risk of keratoconus [IVW: odds ratio (OR) = 0.382; 95% confidence interval (CI) = 0.261–0.560; p = 8.162 × 10(−7)]. Genetically predicted lower proinsulin levels were potentially linked to a higher risk of keratoconus (IVW: OR = 0.739; 95% CI = 0.568–0.963; p = 0.025). In addition, genetically predicted type 2 diabetes negatively correlated with keratoconus (IVW: BMI-unadjusted: OR = 0.869; 95% CI = 0.775–0.974, p = 0.016; BMI-adjusted: OR = 0.880, 95% CI = 0.789–0.982, p = 0.022). These associations were further corroborated by the evidence from all sensitivity analyses. CONCLUSION: These findings provide genetic evidence that higher fasting glucose levels are associated with a lower risk of keratoconus. However, further studies are required to confirmed this hypothesis and to understand the mechanisms underlying this putative causative relationship.