Experimental gerontology · 2026
Exploring the causal link between long-term elevated plasma caffeine levels and age-related eye diseases using Mendelian randomization.
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Dong Hao, Ding Qiang, Liu Mei
Аннотация
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; pFDR < 0.001), wet AMD (OR, 0.582; 95% CI, 0.433-0.781; pFDR = 0.001), ARC (OR, 0.812; 95% CI, 0.720-0.916; pFDR = 0.001), and primary open-angle glaucoma (POAG) (OR, 0.753; 95% CI, 0.633-0.896; pFDR = 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.
NOVELTY & IMPACT STATEMENTS: This study provides novel evidence on the long-term effects of caffeine on age-related eye diseases, including age-related macular degeneration (AMD), age-related cataract (ARC), and primary open-angle glaucoma (POAG). Unlike previous studies that used imprecise measures of caffeine exposure, such as caffeinated beverage intake, we utilized fasting plasma caffeine levels, offering a more accurate assessment of individual exposure. Through Mendelian randomization, we demonstrate that long-term caffeine exposure is independently associated with reduced risks of AMD and ARC, and is also linked to a lower risk of POAG, with approximately half of this effect mediated through intraocular pressure (IOP) reduction. Our findings suggest that caffeine could play a protective role in ocular health, offering new insights into potential prevention strategies for age-related eye diseases.
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; pFDR < 0.001), wet AMD (OR, 0.582; 95% CI, 0.433-0.781; pFDR = 0.001), ARC (OR, 0.812; 95% CI, 0.720-0.916; pFDR = 0.001), and primary open-angle glaucoma (POAG) (OR, 0.753; 95% CI, 0.633-0.896; pFDR = 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.
NOVELTY & IMPACT STATEMENTS: This study provides novel evidence on the long-term effects of caffeine on age-related eye diseases, including age-related macular degeneration (AMD), age-related cataract (ARC), and primary open-angle glaucoma (POAG). Unlike previous studies that used imprecise measures of caffeine exposure, such as caffeinated beverage intake, we utilized fasting plasma caffeine levels, offering a more accurate assessment of individual exposure. Through Mendelian randomization, we demonstrate that long-term caffeine exposure is independently associated with reduced risks of AMD and ARC, and is also linked to a lower risk of POAG, with approximately half of this effect mediated through intraocular pressure (IOP) reduction. Our findings suggest that caffeine could play a protective role in ocular health, offering new insights into potential prevention strategies for age-related eye diseases.