Mendelian randomization reveals probucol’s preventive role in Behçet’s disease via circulating metabolites

Abstract Behçet’s disease (BD) is a chronic, recurrent condition for which effective preventive medications are currently lacking. This disease often disrupts lipid metabolism, adversely affecting vascular endothelial function. Exploring preventive strategies, such as lipid-lowering medications, is crucial. Probucol, known for its lipid-lowering properties, emerges as a promising candidate. By inhibiting the ATP-binding cassette transporter A1 (ABCA1), probucol is hypothesized to regulate circulating metabolites, potentially reducing the risk of BD. This study employs Mendelian randomization (MR) to evaluate probucol’s impact on BD and investigate its preventive potential through the modulation of circulating metabolites. For this MR study, we selected single nucleotide polymorphisms (SNPs) associated with probucol as instrumental variables and conducted a positive control analysis with SNPs linked to high-density lipoprotein (HDL) to validate our instrument selection. The study was structured in two steps: first, using probucol’s eQTLs to estimate its causal effect on circulating metabolites; second, using SNPs linked to these metabolites to assess their causal impact on Behcet’s disease risk. To ensure the robustness and validity of our findings, we employed several MR methods, including the Inverse Variance Weighted (IVW) approach, heterogeneity tests, and pleiotropy analysis. This study identified a total of 30 SNPs associated with BD, 7502 SNPs linked to circulating metabolites, and 1,049 SNPs associated with BD from circulating metabolites, all derived from ABCA1 expression quantitative trait loci (eQTL) data. Utilizing Mendelian randomization (MR) analysis, it was confirmed that probucol leads to a reduction in concentrations of cholesterol esters in HDL, consistent with findings from randomized drug trials (odds ratio [OR] = 0.932, 95% confidence interval [CI] 0.907–0.958, P < 0.001). Furthermore, the study demonstrated that probucol significantly decreased the risk of BD with an OR of 0.496 (95% CI 0.283–0.868, P = 0.014). Among 123 assessed circulating metabolites, thirty-six were found to be associated with probucol. Notably, probucol demonstrated a notable reduction in very large HDL particle concentrations (OR = 0.917, 95% CI 0.889–0.947, P < 0.001), contributing to approximately 10.407% of its overall impact on decreasing BD risk. This study establishes that probucol significantly lowers the risk of BD by reducing very large HDL particle concentrations. It provides a genetic basis for considering probucol as a potential therapeutic option for BD high risk individuals.