Revealing the genetic and immunological crosstalk between SLE and ccRCC: An integrative genomic analysis approach

Although systemic lupus erythematosus (SLE) and clear cell renal cell carcinoma (ccRCC) are clinically distinct, emerging evidence suggests they may share underlying genetic and immunoregulatory mechanisms. However, the specific molecular basis of their potential comorbidity has not been clearly defined, and no prior study has comprehensively investigated their shared genomic architecture. To fill this critical knowledge gap, we conducted the first integrative genome-wide analysis to identify common susceptibility loci, pleiotropic genes, and convergent biological pathways between SLE and ccRCC. Utilizing large-scale genome-wide association studies summary data from European populations, we employed a combination of methods including LDSC, PLACO, MAGMA, Summary data-based Mendelian randomization , and HyPrColoc, alongside functional annotation and pathway enrichment analyses via FUMA and Metascape. We identified a significant positive genetic correlation between SLE and ccRCC (Rg = 0.287, P = 1.5 × 10-4), along with 11 pleiotropic loci, notably including colocalization signals at 3q26.2 and 11q22.3. We further identified 63 pleiotropic genes, with AKT1, ERBB2, and STAT1 functioning as key network hubs associated with the PI3K/Akt, NF-κB, and JAK-STAT pathways. Immunological colocalization analysis indicated that CD24⁺IgD⁺CD38⁻ B cells and unswitched memory B cells may constitute potential comorbid subpopulations. Summary data-based Mendelian randomization analysis further revealed CASP9 as a promising therapeutic target for comorbidity intervention. Overall, this study identified pleiotropic loci and key hub genes enriched in immune-oncogenic pathways, including PI3K/Akt, NF-κB, and JAK-STAT, and proposed potential therapeutic targets, thereby providing a concrete basis for understanding the comorbidity mechanisms of SLE and ccRCC and informing future precision interventions.