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Exploring the causal link between long-term elevated plasma caffeine levels and age-related eye diseases using Mendelian randomization
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DOI：10.1016/j.exger.2026.113106.png)
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Abstract
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Objective Experimental evidence suggests that caffeine has the potential to reduce the risk of age-related eye diseases (AREDs). However, there is a lack of population-based evidence directly assessing whether long-term caffeine exposure benefits these conditions. In this study, we employ Mendelian randomization (MR) to evaluate the causal effects of long-term elevated plasma caffeine levels (PCL) on AREDs, including age-related macular degeneration (AMD), age-related cataract (ARC), and glaucoma. Methods and analysis Single-nucleotide polymorphisms strongly associated with PCL and located near the CYP1A2 and AHR genes, both key in caffeine metabolism, were selected as instrumental variables. The MR analyses then calculated the Wald ratio for each variant, with variant-specific estimates combined through a multiplicative random effects meta-analysis. Results Our MR analysis showed that higher genetically predicted PCL were significantly associated with a reduced risk of dry AMD (odds ratio [OR], 0.651; 95% confidence interval [CI], 0.527-0.805; p(FDR) < 0.001), wet AMD (OR, 0.582; 95% CI, 0.433-0.781; p(FDR) = 0.001), ARC (OR, 0.812; 95% CI, 0.720-0.916; p(FDR) = 0.001), and primary open-angle glaucoma (POAG) (OR, 0.753; 95% CI, 0.633-0.896; p(FDR) = 0.002). Notably, an estimated 54.05% (95% CI: 19.25%-88.84%) of the protective effect of PCL on POAG was mediated through reduced intraocular pressure (IOP). Conclusion This MR study provides evidence that long-term higher plasma caffeine levels may reduce the risk of age-related eye diseases, including AMD, ARC, and POAG. Notably, approximately half of the protective effect of PCL on POAG is mediated through IOP reduction.
Keywords:
Caffeine
Age-related eye diseases
Mendelian randomization
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