Abstract
Background: The current pharmacological treatments for Immunoglobulin A nephropathy (IgAN) demonstrate limited effectiveness and may cause serious side effects. This study aimed to explore novel potential drug targets for IgAN. Methods: We utilized summarized data from a recent genome-wide association study on IgAN, cis-expression quantitative trait loci data for druggable genes obtained from the eQTLGen Consortium, and DNA methylation quantitative trait loci data derived from the GoDMC database. Two-sample Mendelian randomization (MR) analysis, Bayesian colocalization, and mediation analysis through a two-step MR approach were performed to investigate their causal relationships. Results: Two-sample MR and colocalization analyses demonstrated that the expression of HLA-DPA1 and C4A was associated with an increased risk of IgAN. In contrast, TUBB, CYP21A2, and C4B were associated with a decreased risk of IgAN. Mediation analysis revealed that the expression of HLA-DPA1 acted as a mediator in the potential causal relationship between three DNA methylation sites (cg01140143, cg08898074, and cg12168509) and IgAN, with mediated proportions of 33.74% (95% CI 1.64-73.27), 41.67% (95% CI 20.78-66.97), and 50.34% (95% CI 27.89-74.76), respectively. Conclusions: Several druggable genes and DNA methylation sites were identified to show potential causal associations with IgAN risk and may be targeted for drug development. Nevertheless, additional experimental validation is warranted to clarify the specific roles of DNA methylation and the identified druggable genes in the pathogenesis of IgAN.