Genetically Proxied Antidiabetic Drug Target and Primary Open-Angle Glaucoma: A Mendelian Randomization Study

Background and Aims: Observational studies suggest that antidiabetic drugs may lower POAG risk; while the causal relationship remains unclear. Naturally occurring variation in genes encoding antidiabetics drug targets can be used as proxies to investigate long-term therapeutic effect of these drugs on POAG risk. Methods: We performed a two-sample Mendelian randomization study to evaluate the potential effect of antidiabetic drug targets on POAG in Europeans and East Asians. To proxy antidiabetic drugs (ABCC8, PPARG, GLP1R, SLC5A2), we leveraged genetic variants located near or within drug target genes that were associated with HbA1c. The validity of our ancestry-specific genetic instrument was checked with multipul positive control outcomes. Genetic summary statistics of POAG from the International Glaucoma Genetics Consortium, Global Biobank Meta-analysis Initiative, and FinnGen consortia were analyzed for Europeans (38,164 cases and 1,576,179 controls) and East Asians (16,650 cases and 288,833 controls) separately. Inverse-variance weighted random-effects models were used as primary method. Results: MR results provided consistent evidence of a protective effect of ABCC8 inhibition on POAG using data sets from IGG, GBMI, and FinnGen. Genetically predicted one-standard deviation reduction in HbA1c from ABCC8 inhibition were significant associated with lower risk of POAG in Europeans (OR = 0.211, 95% CI: 0.133-0.333; p < 0.001) and East Asians (OR = 0.070, 95% CI: 0.011-0.459; p = 0.0056). The association between genetically predicted ABCC8 inhibition and risk of POAG was mainly mediated through intraocular pressure. No association was found for PPARG, SLC5A2, or GLP1R. Sensitivity analyses supported this observation. Conclusions: We found a protective effect of genetically proxied ABCC8 inhibition on POAG risk in both Europeans and East Asians, highlighting ABCC8 as a promising candidate drug target for POAG, and mechanisms underlying the protective effect should also be investigated.