Possible Causal Association between Type 2 Diabetes and Glycaemic Traits in Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomisation Study

Abstract

Existing literature suggests a controversial relationship between type 2 diabetes mellitus (T2D) and glaucoma. This study aimed to examine the potential causal connection between T2D and glycaemic traits (fasting glucose [FG] and glycated haemoglobin [HbA1c] levels) as exposures to primary open-angle glaucoma (POAG) in multi-ethnic populations. Single-nucleotide polymorphisms associated with exposure to T2D, FG, and HbA1c were selected as instrumental variables with significance (p < 5.0 × 10^-8) from the genome-wide association study (GWAS)-based meta-analysis data available from the BioBank Japan and the UK Biobank (UKB). The GWAS for POAG was obtained from the meta-analyses of Genetic Epidemiology Research in Adult Health and Aging and the UKB. A two-sample Mendelian randomisation (MR) study was performed to assess the causal estimates using the inverse-variance weighted (IVW) method, and MR-Pleiotropy Residual Sum and Outlier test (MR-PRESSO). Significant causal associations of T2D (odds ratio [OR] = 1.05, 95% confidence interval [CI] = [1.00-1.10], p = 0.031 in IVW; OR = 1.06, 95% CI = [1.01-1.11], p = 0.017 in MR-PRESSO) and FG levels (OR = 1.19, 95% CI = [1.02-1.38], p = 0.026 in IVW; OR = 1.17, 95% CI = [1.01-1.35], p = 0.041 in MR-PRESSO) with POAG were observed, but not in HbA1c (all p > 0.05). The potential causal relationship between T2D or FG and POAG highlights its role in the prevention of POAG. Further investigation is necessary to authenticate these findings.

Keywords: fasting glucose; mendelian randomisation; primary open-angle glaucoma; single-nucleotide polymorphisms; type 2 diabetes.

Figure 1

Diagram of two-sample Mendelian randomisation analysis. Abbreviation: HbA1c, glycated haemoglobin; SNP, Single nucleotide polymorphism.

Figure 2

Forest plot of causal associations of T2D on glaucoma. Abbreviations: T2D, type 2 diabetes; IVW, inverse-variance weighted; SIMEX, Simulation Extrapolation; MR–PRESSO, MR- pleiotropy residual sum and outlier test; OR, odds ratio; CI, confidence interval.

Figure 3

Scatter plots of MR tests assessing the effect of T2D on glaucoma. Abbreviations: T2D, type 2 diabetes; IVW, inverse-variance weighted; SIMEX, Simulation Extrapolation; MR, Mendelian randomisation. Light blue, light green, dark blue, and dark green regression lines represent the IVW, MR–Egger (SIMEX), MR–Egger, and weighted median estimate, respectively.

Figure 4

Forest plot of causal associations of FG and HbA1c on glaucoma. Abbreviations: FG, fasting glucose; IVW, inverse-variance weighted; SIMEX, Simulation Extrapolation; MR–PRESSO, MR-pleiotropy residual sum and outlier test; OR, odds ratio; CI, confidence interval, HbA1c, glycated haemoglobin.

Figure 5

Scatter plots of MR tests assessing the effect of FG and HbA1c on glaucoma. Abbreviations: FG, fasting glucose; IVW, inverse-variance weighted; SIMEX, Simulation Extrapolation; HbA1c, glycated haemoglobin; MR, Mendelian randomisation. Light blue, light green, dark blue, and dark green regression lines represent the IVW, MR–Egger (SIMEX), MR–Egger, and weighted median estimate, respectively.