Metabolomic signatures and causal effects of circulating metabolites on age-related cataract

Age-related cataract (ARC) is a leading cause of visual impairment and blindness among older adults, yet effective pharmacological options remain limited. This study aimed to identify candidate circulating metabolic biomarkers and pathways associated with ARC risk.

Genetic data for blood metabolites and ARC were derived from three metabolite genome-wide association studies (GWASs) and FinnGen. Mendelian randomization (MR) analyses assessed associations between 121 metabolites and ARC. UK Biobank cohort analyses evaluated whether MR-identified associations were observed in longitudinal real-world data. Bioinformatics and molecular docking analyses were used to explore potential mechanistic pathways and applicability.

MR analyses identified protective associations of 1,5-anhydroglucitol (odds ratio (OR) = 0.60, 95% confidence interval (CI), 0.43-0.82), triglycerides in low-density lipoprotein (LDL) (OR = 0.95, 95% CI, 0.92-0.98), linoleic acid (OR = 0.92, 95% CI 0.88-0.97), and polyunsaturated fatty acids (PUFAs) (OR = 0.93, 95% CI, 0.89-0.97) with ARC. In cohort analysis, linoleic acid (hazard ratio (HR) = 0.96, 95% CI, 0.94-0.98) and PUFAs (HR = 0.96, 95% CI, 0.94-0.98) were associated with a lower incident ARC risk, whereas triglycerides in LDL was not significant overall, although an inverse association was observed in participants aged ≥ 60 years (HR = 0.97, 95% CI, 0.95-0.99). Bioinformatics analyses identified candidate genes and pathways, and docking suggested potential interactions between linoleic acid and candidate proteins.

Linoleic acid and PUFAs showed consistent inverse associations with ARC. Further experimental studies are needed to validate their biological relevance and clinical utility.