Causal Relationship Between Glycated Hemoglobin (HbA1c) and Cataract: A Bidirectional Mendelian Randomization Study

Area of Science:

• Ophthalmology
• Endocrinology
• Genetics

Background:

• Epidemiological studies suggest a link between glycated hemoglobin (HbA1c) and cataracts.
• The precise causal relationship between HbA1c and cataract development remains undetermined.

Purpose of the Study:

• To investigate the causal effect of HbA1c on cataract formation using a bidirectional Mendelian randomization (MR) analysis.
• To explore the reverse causal relationship from cataracts to HbA1c.

Main Methods:

• Utilized a bidirectional MR analysis with data from the IEU OpenGWAS database.
• Employed inverse-variance weighted (IVW) estimation as the primary method, supported by sensitivity analyses for horizontal pleiotropy.
• Used single nucleotide polymorphisms (SNPs) as instrumental variables for HbA1c and cataract.

Main Results:

• A significant causal effect of HbA1c on cataract risk was identified (OR = 1.022, P = 2.95E-06).
• No significant causal effect of cataract on HbA1c was found in the reverse analysis.
• Sensitivity analyses indicated minimal distortion from horizontal pleiotropy; IV-associated genes were enriched in carbohydrate metabolism and autophagy pathways.
• In vitro studies showed elevated HbA1c increased ROS production, reduced SOD activity, and induced apoptosis.

Conclusions:

• The MR analysis provides strong evidence for a causal role of HbA1c in cataract development.
• Tight glycemic control is clinically important for mitigating cataract risk.