Integrative Identification of Comorbid Genes Linking ANCA-Associated Vasculitis and Bladder Cancer Using Single-Cell Transcriptomics and Mendelian Randomisation
Year: 2026
Type: article
Abstract: Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an immune-mediated inflammatory disorder, and bladder cancer is a common urologic malignancy. Epidemiological evidence shows AAV patients have a markedly higher risk of bladder cancer (OR = 3.84; 95% CI: 2.72–5.42). However, the shared genetic basis of this comorbidity remains unclear. Here, we integrate single-cell transcriptomics and Mendelian randomisation to explore its molecular architecture. Methods: Single-cell RNA-seq data for ANCA-associated glomerulonephritis (GSE303481) and bladder cancer (GSE222315) were obtained from the GEO. We identified overlapping monocyte DEGs after Seurat preprocessing. Mendelian randomisation was conducted using five complementary methods (IVW, MR-Egger, weighted median, and simple and weighted mode) with comprehensive sensitivity tests. Further analyses covered functional enrichment, gene networks, miRNA prediction, and pseudotime trajectories. Results: After stringent quality control, 138,457 and 96,017 cells were retained in the AAV and bladder cancer datasets, respectively. Monocytes displayed the most pronounced transcriptional alterations, yielding 3288 overlapping candidate genes. MR analysis identified 94 genes with putative causal effects on AAV and 80 on bladder cancer, and intersection analysis identified SP1 and GET4 as shared candidate genes, with SP1 showing a protective association and GET4 a risk association for both diseases. Both genes participated in transcriptional regulatory programmes and exhibited extensive miRNA-mediated regulatory interactions. Pseudotime analysis further revealed disease-specific dynamic expression trajectories of both genes during monocyte differentiation in both disease contexts. Conclusions:SP1 and GET4 may represent genetically supported shared susceptibility factors whose dysregulation may contribute to AAV–bladder cancer comorbidity. Our findings provide insights into a monocyte-centric transcriptional programme characterised by disease-specific regulatory dynamics and immunoinflammatory crosstalk that may underlie the pathophysiological basis of AAV–bladder cancer comorbidity. Further experimental and independent studies are warranted to validate these findings.
DOI: 10.3390/cimb48111182
Authors: Desheng Zhang, Yunjin Bai, Ping Han
Institutions: Sichuan University, West China Hospital of Sichuan University
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,654
OpenAlex ID: W7225619657