Causal relationship between lipid-lowering drugs and ocular disorders: A drug-targeted Mendelian randomization study

Background Most ocular diseases are associated with lipid metabolism, but the exact mechanisms are unclear. Statins, PCSK9 inhibitors and NPC1L1 inhibitors are common lipid-modulating agents. The aim of this study was to explore the causal relationship between common lipid-lowering drugs and ocular diseases through Mendelian randomization analysis. Methods In this study, we used the summary-data-based Mendelian randomization (SMR) method and inverse-variance-weighted Mendelian randomization (IVW-MR). Low-density lipoprotein cholesterol (LDL-C) was used as a biomarker. We then obtained instrumental variables (IVs) from the Global Lipids Genetics Consortium (GLGC) (n = 173082) and UK Biobank (n = 440546). The 3-Hydroxy-9-methylglutaryl-coenzyme A reductase (HMGCR) expression quantitative trait loci (eQTL) was obtained from a cohort study containing 31,684 blood samples. Summary data for ocular diseases were obtained from the Integrative Epidemiology Unit (IEU) database. Results IVW-MR showed that statins increased the risk of allergic conjunctivitis (OR = 1.96, 95% CI: 1.30–2.95, P  = 0.001) and diabetic retinopathy (OR = 2.58, 95% CI: 1.67–3.99, P  < 0.001). PCSK9 inhibitors reduced the risk of allergic conjunctivitis (OR = 0.67, 95% CI: 0.47–0.95, P  = 0.02) but increased the risk of glaucoma (OR = 1.23, 95% CI: 1.06–1.43, P  = 0.006). The SMR approach showed that inhibition of HMGCR significantly elevated the risk of allergic conjunctivitis (OR = 1.28, 95% CI: 1.11–1.45, P  < 0.001) and diabetic retinopathy (OR = 1.56, 95% CI: 1.33–1.84, P  < 0.001). Conclusion The study found that statin elevated the risk of allergic conjunctivitis and diabetic retinopathy. PCSK9 inhibitors reduced the risk of allergic conjunctivitis but elevated the risk of glaucoma. But more mechanisms remain to be further explored.