Serum Klotho Levels and Major Age-Related Ocular Disorders: A Cross-Sectional and Genetic Association Study

Purpose: To examine the association between serum Klotho levels and the prevalence of glaucoma, cataract, and retinal disease, and to explore the potential causal relationship between Klotho and glaucoma. Methods: Data from the 2007-2008 National Health and Nutrition Examination Survey were used, including participants aged 40 years and older. Serum Klotho levels were analyzed both as a continuous variable and by quartiles. Logistic regression analysis was performed to assess the associations between serum Klotho levels and ocular disorders. Bidirectional two-sample Mendelian randomization (MR) was used to assess a causal relationship between serum Klotho and glaucoma. Results: A total of 2952 participants were included in the glaucoma analysis. Higher serum Klotho levels were positively associated with glaucoma risk (odds ratio [OR] = 1.05 per 100 pg/mL increase; 95% confidence interval [CI], 1.01-1.09; P = 0.006). Individuals in the highest Klotho quartile had significantly greater glaucoma risk (OR = 1.47; 95% CI, 1.07-2.03; P = 0.02). MR analyses found no evidence of a causal relationship between Klotho and glaucoma in either direction. No significant associations were observed between serum Klotho and cataract (n = 2950) or retinal disease (n = 2637). Conclusions: Higher circulating Klotho levels are associated with an increased prevalence of glaucoma, suggesting a more complex relationship than the previously presumed protective role of Klotho in glaucoma. The lack of genetic evidence for causality suggests this systemic-level association is unlikely to be causal, highlighting the need to investigate whether circulating Klotho reflects distinct processes from those involving its local expression within ocular tissues. Translational Relevance: These findings highlight the potential of circulating Klotho as a systemic biomarker for glaucoma risk assessment, while emphasizing that its role in ocular pathophysiology requires separate investigation of local expression and function.