Causal relationships between type 2 diabetes, glycemic traits and keratoconus

PurposeThe 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.MethodsWe 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).ResultsResults 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 x 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.ConclusionThese 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.

Automated summary

This study used Mendelian randomization design to assess the potential causal relationships between type 2 diabetes, glycemic traits, and the risk of keratoconus. The findings suggest that higher fasting glucose levels are associated with a lower risk of keratoconus, while lower proinsulin levels may be linked to a higher risk. Additionally, genetically predicted type 2 diabetes is negatively correlated with keratoconus risk. These associations were supported by sensitivity analyses.