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

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.

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.

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).

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.

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.