ACP2 Protects Against Multiple Sclerosis by Modulating HDL-C: Real-World Observational And Mendelian Randomization Study

Background: The role of cholesterol metabolites in multiple sclerosis (MS) remains controversial regarding pathogenic or protective effects.Objective: Investigate nonlinear and causal cholesterol metabolite-MS relationships and identify upstream gene regulators with therapeutic potential.Methods: Analyzed UK Biobank data using logistic regression for nonlinear associations between HDL-C, LDL-C, total cholesterol, and MS risk. Univariable and multivariable Mendelian randomization (MR) assessed causal effects of these metabolites and brain/blood tissue gene expression on MS.Results: HDL-C, LDL-C, and total cholesterol exhibited nonlinear, threshold-dependent associations with MS risk. MR confirmed a causal effect of elevated HDL-C on increased MS risk. Sequential MR identified NR1H3 and ACP2 as regulators lowering HDL-C and reducing MS risk. Multivariable MR indicated ~16%-20% of this protection is mediated via HDL-C reduction. ACP2 showed consistent protective effects in both blood and brain tissues.Conclusion: Elevated HDL-C causally increases MS risk above a threshold. ACP2 acts protectively by lowering HDL-C, representing a potential therapeutic target. These findings offer novel lipid-MS axis insights and highlight integrating genetic and tissue-specific data for disease mechanisms.