Integrated Mendelian Randomization and Single-Cell Transcriptomics Reveal T Cell Immune Mechanisms in Systemic Lupus...

Objective: Patients with systemic lupus erythematosus (SLE) exhibit elevated malignancy risk, with increased bladder cancer incidence. This study integrated Mendelian randomization (MR) with single-cell sequencing (scRNA-seq) to nominate exploratory prioritized candidate genes in SLE-bladder cancer comorbidity and their T cell regulatory roles. Methods: Single-cell datasets for SLE (GSE266852) and bladder cancer (GSE222315) were retrieved from GEO. Quality control, clustering, and annotation were performed using Seurat. T cell differentially expressed genes were intersected for bidirectional two-sample MR using IEU Open GWAS statistics. Heterogeneity, pleiotropy, and sensitivity analyses assessed robustness. GeneMANIA, miRNA databases, and CTD were used for network and functional analyses. Wilcoxon tests and Monocle 2 were used to characterize expression and T cell differentiation trajectories. Results: Cross-disease intersection nominated 1010 candidate genes. In an exploratory MR screen (uncorrected p < 0.05), four candidate genes were nominated (GBP3, LMAN1, SLC40A1, MIS18BP1); none survived FDR correction in both directions. At the uncorrected threshold, LMAN1 showed a shared risk direction (OR > 1) and MIS18BP1 a protective direction (OR < 1). Both showed significant T cell differential expression (p < 0.001) and elevated late differentiation expression. LMAN1 was involved in COPII vesicle transport; MIS18BP1 in CENP-A chromatin assembly. Twenty high-confidence miRNAs targeted each gene. CTD indicated liver injury associations and cisplatin/cyclosporine interactions. Conclusions: LMAN1 and MIS18BP1 are proposed as hypothesis-generating exploratory candidate genes in SLE-bladder cancer comorbidity, potentially involved in immune dysregulation through T cell terminal differentiation modulation. This study provides preliminary evidence suggestive of autoimmune-malignancy comorbidity mechanisms.