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Cross-phenotype integration of eQTL-based Mendelian randomization and transcriptomics prioritizes BMP2K in IgA
Su Peng1,2, Chuang Xie1,2, Chuang Qian1,2
1Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Objective:
To prioritize candidate genes and compounds potentially associated with IgA vasculitis with nephritis (IgAVN) by integrating genetic and transcriptomic evidence across IgAVN, IgA vasculitis (IgAV), and IgA nephropathy (IgAN), followed by preliminary cellular and pharmacological validation.
Methods:
Expression quantitative trait locus (eQTL)-based two-sample Mendelian randomization (MR) was performed using FinnGen summary statistics for IgAVN, IgAV, and IgAN. MR-prioritized genes were integrated with differentially expressed genes from the IgAVN transcriptomic dataset GSE102114. Fisher's method was used to combine convergent evidence, and exploratory immune cell-specific single-cell eQTL-based MR was conducted to identify potential cell-type-relevant signals. Candidate compounds were screened using drug-signature analysis and evaluated by molecular docking. BMP2K mRNA expression was measured by RT-qPCR in peripheral blood mononuclear cells (PBMCs) from children with IgAVN (n = 13), children with IgAV (n = 10), and healthy controls (n = 13). Functional and pharmacological effects were evaluated in lipopolysaccharide (LPS)-stimulated THP-1 cells using siRNA-mediated knockdown, CCK-8, RT-qPCR, Western blotting, and ELISA.
Results:
MR analysis identified 124 genes with nominally significant risk-increasing associations with IgAVN, 132 with IgAV, and 119 with IgAN. Integration with IgAVN transcriptomic data prioritized four candidate genes: BMP2K, GYPB, IGFBP7, and MISP3. Among these, BMP2K was the only gene supported across all three IgA-related phenotypes and the IgAVN transcriptomic dataset. BMP2K mRNA expression was significantly higher in PBMCs from children with IgAVN than in healthy controls. Exploratory single-cell eQTL-based MR suggested a nominal monocyte-related association between genetically predicted BMP2K expression and IgAVN risk. In THP-1 cells, BMP2K knockdown reduced LPS-induced secretion of IL-6, IL-8, and TNF-α. Drug-signature analysis and molecular docking nominated ruboxistaurin as a candidate compound. Ruboxistaurin attenuated LPS-induced inflammatory cytokine expression and secretion and was associated with a statistically significant reduction in BMP2K expression.
Conclusion:
Integrative genetic, transcriptomic, and preliminary experimental evidence prioritized BMP2K as a candidate gene for IgAVN. Ruboxistaurin showed anti-inflammatory activity and was associated with lower BMP2K protein abundance in vitro; however, direct target engagement and BMP2K-specific activity were not established. Larger independent genetic datasets, colocalization analyses, renal tissue validation, and disease-relevant mechanistic models are required.