Inter-Relationships Between Retinal Vascular Caliber, Retinal Nerve Fiber Layer Thickness, and Glaucoma: A Mediation Analysis Approach

PURPOSE: The purpose of this study was to explore the interrelationships among retinal vascular caliber, retinal nerve fiber layer (RNFL), and glaucoma; in particular, whether the relationship between narrower retinal vascular caliber and glaucoma is mediated by thinning of RNFL. METHODS: A total of 9407 participants, including 253 glaucoma and 195 primary open-angle glaucoma (POAG) cases from the Singapore Epidemiology of Eye Diseases Study were included in this study. All participants underwent standardized examinations. Glaucoma was defined according to International Society for Geographical and Epidemiologic Ophthalmology criteria. Logistic regression analyses were used to determine the total direct effects of retinal vascular calibers on glaucoma. Regression-based mediation analyses were used to evaluate the indirect effects of retinal vascular caliber on glaucoma through RNFL thinning. RESULTS: After we adjusted for relevant covariates, narrower retinal arteriolar caliber (per standard deviation [SD], 15.1-μm decrease) was associated with glaucoma (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.06-1.38) and POAG (OR, 1.23; 95% CI, 1.06-1.43). Similarly, narrower retinal venular caliber (per SD, 21.6μm decrease) was associated with glaucoma (OR, 1.51; 95% CI, 1.32-1.73) and POAG (OR, 1.64; 95% CI, 1.41-1.91). In addition, there were significant indirect effects of retinal vascular narrowing on glaucoma through thinning of RNFL (all P < 0.001), with mediated proportion of 36.9% and 12.9% in retinal arteriole- and venule-related analysis, respectively. CONCLUSIONS: Mediation analyses indicated that the effect of retinal vascular narrowing on glaucoma was partially the result of thinning of RNFL. These findings provide additional mechanistic insights linking retinal vascular narrowing and glaucoma.