Abstract
Purpose: Glycated hemoglobin (HbA1c) has been linked to cataract in previous epidemiological observational studies; however, the exact causal relationship between HbA1c and cataract formation remains unclear. Methods: We performed a bidirectional Mendelian randomization (MR) analysis using data from two datasets in IEU OpenGWAS database. Inverse-variance weighted (IVW) estimation was used as the primary analysis, followed by the application of four complementary methods to detect and correct the effect of horizontal pleiotropy. Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) for HbA1c or cataract. Comparable results were obtained by methods such as Cochran's Q. Enrichment analysis was performed on IV-associated genes. Validation analysis based on cell lines was performed to reveal the effect of HbA1c in vitro. Results: A total of 183 SNPs were used as significant IVs for HbA1c in forward MR analysis. The results showed that HbA1c was significantly associated with cataracts (odds ratio = 1.022, 95% confidence interval, 1.012-1.031, P = 2.95E-06). However, the causal effect of cataracts on HbA1c was not significant in the reverse MR analysis. The IVW method provided the ideal results in current bidirectional MR analysis. Horizontal pleiotropy was unlikely to distort the causal estimates according to the sensitivity analysis. IV-associated genes were mainly enriched in carbohydrate metabolism function and autophagy pathway. Elevated HbA1c levels significantly increased ROS production, reduced SOD activity, and induced apoptosis. Conclusions: Findings of this MR study supported a causal effect of HbA1c on cataract, underscoring the clinical importance of tight glycemic control as a strategy for reducing cataract risk. Translational relevance: With the further study of HbA1c, this study suggests that there is a causal relationship between HbA1c and cataract and suggests that strict blood glucose control can be a strategy to reduce the risk of cataracts.