Association between Circulating Ketone Bodies and Primary Open-Angle Glaucoma and Related Ocular Parameters

Ketone bodies are key metabolic intermediates with both neuroprotective and pro-oxidative properties; however, their role in glaucoma remains unclear. This study aimed to investigate associations between circulating ketone bodies and the incidence of primary open-angle glaucoma (POAG), as well as related ocular parameters, in the UK Biobank.

Combined cross-sectional analysis and prospective cohort study.

A total of 456 499 participants were included in the cohort analysis; 104 225 were included in the baseline intraocular pressure (IOP) analysis, 41 495 in the baseline ganglion cell complex (GCC) thickness analysis, and 39 498 in the IOP-adjusted GCC thickness analysis.

Circulating ketone bodies were quantified using nuclear magnetic resonance-based metabolomics. Cox proportional hazards models were used to estimate hazard ratios for POAG incidence. Linear regression models assessed associations with baseline IOP and GCC thickness. Restricted cubic spline models were applied to evaluate dose-response relationships, and subgroup analyses were conducted to explore potential effect modification.

Incidence of POAG.

During follow-up, 2330 participants developed POAG. Higher circulating ketone body levels were associated with an increased incidence of POAG after full adjustment (hazard ratio: 1.93, 95% confidence interval [CI]: 1.25-2.99, P = 0.003). Elevated ketone body levels were also associated with higher baseline IOP (β = 1.84, 95% CI: 1.57-2.10, P < 0.001) and thinner GCC both before (β = -1.62, 95% CI: -2.66 to -0.57, P = 0.002) and after IOP adjustment (β = -1.48, 95% CI: -2.53 to -0.42, P = 0.006), suggesting associations that are partially IOP-independent.

Elevated circulating ketone body levels were associated with a higher incidence of POAG and related ocular phenotypes. Circulating ketone body levels may serve as a potential biomarker of systemic metabolic dysregulation associated with increased POAG susceptibility.Financial Disclosure(s)Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.