Causal effect of gut microbiota on pancreatic cancer: A Mendelian randomization and colocalization study

The causal relationship between gut microbiota (GM) and pancreatic cancer (PC) remains unclear. This study aimed to investigate the potential genes underlying this mechanism. GM Genome-wide association study (GWAS) summary data were from the MiBioGen consortium. PC GWAS data were from the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) GWAS Catalogue. To detect the causal relationship between GM and PC, we implemented three complementary Mendelian randomization (MR) methods: Inverse Variance Weighting (IVW), MR-Egger and Weighted Median, followed by sensitivity analyses. Furthermore, we integrated GM GWAS data with blood cis-expression quantitative trait loci (eQTLs) and blood cis-DNA methylation QTL (mQTLs) using Summary data-based Mendelian Randomization (SMR) methods. This integration aimed to prioritize potential GM-affecting genes through SMR analysis of two molecular traits. PC cis-eQTLs and cis-mQTLs were summarized from The Cancer Genome Atlas (TCGA) data. Through colocalization analysis of GM cis-QTLs and PC cis-QTLs data, we identified common genes that influence both GM and PC. Our study found a causal association between GM and PC, including four protective and five risk-associated GM [Inverse Variance Weighted (IVW), p < 0.05]. No significant heterogeneity of instrumental variables (IVs) or horizontal pleiotropy was found. The gene SVBP was identified as a GM-affecting gene using SMR analysis of two molecular traits (FDR<0.05, P_HEIDI>0.05). Additionally, two genes, MCM6 and RPS26, were implicated in the interaction between GM and PC based on colocalization analysis (PPH4>0.5). In summary, this study provides evidence for future research aimed at developing suitable therapeutic interventions and disease prevention.