Circulating inflammatory cytokines and risk of bladder cancer: a Mendelian randomization study

Background: Epidemiological evidence has verified the relationship between inflammatory biomarkers and bladder cancer (BCa). It is uncertain whether these associations are causal. Here, we performed Mendelian randomization (MR) analyses to systematically evaluate the causal relationship between the wide panel of inflammatory cytokines and BCa risk. Methods: The Exposure data were extracted from the genome-wide association study (GWAS) of 47 circulating cytokines. The cis-protein quantitative trait locus (cis-pQTL) and cis-expression quantitative trait locus (cis-eQTL) were used as instrumental variables. The outcome data were obtained from the United Kingdom Biobank. Two-sample MR analyses were performed to assess the causal inference of inflammatory cytokines on BCa risk, followed by sensitivity analyses to overcome the disadvantages of inverse-variance weighted method. Results: We observed Eotaxin has significant causal effects on BCa (cis-pQTL: OR= 0.997, 95% CI =0.995-0.999, p=0.002; cis-eQTL: OR= 0.996, 95% CI =0.993-0.998, p =0.001) in both the cis-pQTL and cis-eQTL definition. Further single-cell analysis revealed Eotaxin was predominantly expressed in inflammatory-cancer-associated fibroblasts (iCAFs) but not in myo-cancer-associated fibroblasts (mCAFs). Besides, CCL11 expression was significantly higher in normal tissue iCAFs than in BCa iCAFs. Conclusions: Our study provides supportive evidence on the role of specific cytokines in cancer aetiology. CCL11+ iCAFs may be a subtype of iCAFs that inhibit tumor progression. Further studies are needed to investigate the potential mechanisms of cytokines as drug targets for cancer prevention.