Circulating micronutrients as protective factors for the retinal structure and vasculature: Mendelian randomization...

Epidemiological data and clinical trials have suggested that micronutrients may preserve retinal integrity by mitigating neurodegenerative alterations and microvascular damage. To strengthen the genetic evidence, we investigated the causal effects of various circulating micronutrients (CMs) on retinal imaging parameters using Mendelian randomization (MR) analyses.

Two-sample MR analyses utilized genetic variants as instrumental variables to investigate the effects of 14 CMs on retinal structural parameters including ganglion cell inner plexiform layer (GCIPL) thickness, outer nuclear layer thickness, and retinal nerve fiber layer thickness, as well as retinal vascular parameters comprising vascular density (VD) and fractal dimension (FD). Inverse variance weighted model was employed as the primary analytical method, with 5 sensitivity methods supplemented to confirm the results' robustness.

Genetic predisposition to higher circulating folate levels was robustly associated with increased macular GCIPL thickness (β=0.94, 95% confidence interval (CI): 0.17-1.70, P=0.017), which remained significant (P=0.039) after MRlap correction. While nominal associations were observed between circulating vitamin B12 and vitamin E levels with both VD (vitamin B12: β=0.33, 95% CI: 0.09-0.56, P=0.007; vitamin E: β=0.19, 95% CI: 0.04-0.34, P=0.016) and FD (vitamin B12: β=0.24, 95% CI: 0.05-0.42, P=0.012; vitamin E: β=0.18, 95% CI: 0.04-0.33, P=0.016), these findings warranted a cautious interpretation due to inconsistencies across sensitivity analyses.

Our MR analyses evaluate the complex relationship between CMs and retinal imaging features, suggesting the protective and thus potentially therapeutic effects of folate in maintaining GCIPL thickness. Conversely, the potential associations observed for other micronutrients remain tentative and warrant cautious interpretation and further empirical validation.