Type 2 Diabetes, Fasting Glucose, Hemoglobin A1c Levels and Risk of Primary Open-Angle Glaucoma: A Mendelian Randomization Study

PURPOSE: To evaluate the potential causal associations between type 2 diabetes and fasting glucose and HbA1c levels and the risk of primary open-angle glaucoma (POAG) in European and East Asian populations. METHODS: We selected genetic variants (P < 5 × 10(−8)) for type 2 diabetes (898,130 Europeans; 433,540 East Asians), fasting glucose, and HbA1c (196,991 Europeans; 36,584 East Asians) from three meta-analyses of genome-wide association studies (GWAS). The GWAS for POAG provided summary statistics (192,702 Europeans; 46,523 East Asians). Mendelian randomization (MR) analysis was accomplished using the inverse variance–weighted method, weighted-median method, MR Egger method, and MR-Pleiotropy RESidual Sum and Outlier test. RESULTS: Genetically predicted type 2 diabetes was potentially positively associated with POAG in the European ancestry (body mass index [BMI]–unadjusted: odds ratio [OR] = 1.07, 95% confidence interval [CI], 1.01–1.14, P = 0.028; BMI-adjusted: OR = 1.07, 95% CI, 1.01–1.15, P = 0.035), but not in the East Asian ancestry (BMI-unadjusted: OR = 1.01, 95% CI, 0.95–1.06, P = 0.866; BMI-adjusted: OR = 1.00, 95% CI, 0.94–1.05, P = 0.882). There was no evidence to support a causal association of fasting glucose (European: OR = 1.19, P = 0.157; East Asian: OR = 0.94, P = 0.715) and HbA1c (European: OR = 1.27, P = 0.178; East Asian: OR = 0.85, P = 0.508) levels with POAG. CONCLUSIONS: The causal effect of type 2 diabetes on the risk of POAG is different in European and East Asian populations. The point estimates of fasting glucose and Hb1Ac with POAG are large but not statistically significant, which prompts the question of statistical power.