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 fast-ing 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 x 10-8) for type 2 diabetes (898,130 Euro-peans; 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 Euro-pean 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.