Exploring the causal relationship between vitamin D levels and deficiency with the risk of cataract: A Mendelian Randomisation study

Abstract

Background: Previous observational studies have suggested an association between vitamin D levels and the risk of cataracts. Whilst this correlation has been well reported, there is a lack of causal evidence. Methods: We first conducted an observational study using UK Biobank (UKBB) data to explore the correlation between vitamin D levels and deficiency with incident cataract. To assess causality, we then performed both one-sample and two-sample Mendelian Randomisation (MR) analyses. The one-sample MR used genetic risk scores (GRS) reflecting a genetic predisposition to higher vitamin D levels and vitamin D deficiency, examining its association with incident cataract. The two-sample MR, publicly available summary statistics for vitamin D levels and deficiency were used to investigate their relationship with cataract. Sensitivity analyses using a UKBB meta-analysis for vitamin D in a two-sample MR and a gene-focused analysis using variants in genes with a known role in vitamin D metabolism. Results: The observational analysis showed a statistically significant relationship between both vitamin D levels (OR = 0.998, ln(OR)SE = 3.23x10-4, p = 6.72x10-14) and deficiency (OR = 1.237, ln(OR)SE = 0.022, p = 9.05x10-23) with incident cataract risk. However, there was insufficient evidence to suggest an association between vitamin D supplementation and cataract risk (OR = 0.971, ln(OR)SE = 0.016, p = 0.057). Furthermore, no evidence was found in our one-sample MR analysis to suggest a causal relationship between vitamin D levels (OR = 1.001, ln(OR)SE = 0.002, p = 0.541) or vitamin D deficiency (OR = 1.095, ln(OR)SE = 0.145, p = 0.534) and incident cataract. The inverse variance weighted two-sample MR analysis also showed no evidence to suggest a causal association between vitamin D levels (IVW: OR = 1.122, 95% CI: 0.968-1.301, p = 0.125) or deficiency (IVW: OR= 0.987, 95% CI: 0.959-1.015, p = 0.344) and cataract risk, with consistent results observed using a multi-ethnic cataract cohort. Some evidence was observed between vitamin D levels and increasing cataract risk (Weighted median OR = 1.076, 95% CI: 1.002–1.156, p = 0.045), however, due to sample overlap between the exposure and outcome, datasets should be interpreted with caution. Conclusion: Whilst we identified a correlative association between vitamin D levels and cataract, we found no robust evidence to support a causal relationship between vitamin D levels and deficiency with cataract risk.