Exploring Potential Drug Targets for Pancreatic Cancer Based on Mendelian Randomization

Abstract Objective Genome-wide association studies (GWAS) provide a rich resource for identifying risk factors and biomarkers associated with cancer susceptibility. This study aims to use Mendelian randomization (MR) analyses within the proteome and transcriptome to explore potential protein markers and therapeutic targets for pancreatic cancer. Methods Exposure data were derived from expression quantitative trait loci (eQTL) data from GTEx V8 and the eQTLGen Consortium, covering 838 and 31,684 participants, as well as protein quantitative trait loci (pQTL) data for 3,703 proteins with a sample size of 27,698 participants. The pancreatic cancer GWAS dataset was obtained from the FinnGen Consortium, including 1,626 pancreatic cancer patients and 314,193 controls. The inverse variance weighted(IVW) and Wald ratio were the main analytical methods to assess the causal relationship between the proteome/transcriptome and pancreatic cancer. Cochran's Q test and MR-Egger intercept were used to evaluate heterogeneity and pleiotropy. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction networks revealed functional characteristics and biological relevance. Results A total of 16,059 mRNAs and 1,608 proteins were included in the study. MR analysis using pQTL and eQTL data showed that 88 proteins and 811 mRNAs were causally related to pancreatic cancer based on the IVW and Wald ratio methods. Among these 88 proteins and 811 mRNAs, eight genes overlapped, including HAGH, FGF2, DTD2, IDUA, and CD248, demonstrating consistent causal effects with pancreatic cancer at both the protein and mRNA levels. However, IRF3, PILRA, and AMY2B showed inconsistent effects on pancreatic cancer at the protein and mRNA levels. GO analysis highlighted processes related to cellular transport, and KEGG pathway analysis suggested involvement in metabolic pathways and signaling pathways. Conclusion This study identified key proteins and mRNAs associated with pancreatic cancer, enhancing our understanding of the disease's molecular mechanisms and providing insights for future research and therapeutic development.