Identification of SARS2, PKN1, and IL11RA as causally-associated genes for patients with gastric cancer via immune cell activity: A multi-omics Mendelian randomization study integrating GWAS, eQTL, and pQTL data

BACKGROUND: Gastric cancer (GC) is a highly heterogeneous gastrointestinal malignancy associated with poor prognosis. A comprehensive understanding of its molecular mechanisms is crucial for identifying novel therapeutic targets. This study employed a multi-omics Mendelian randomization (MR) approach to investigate the causal associations among gene expression, protein expression levels, and immune cells in GC risk. METHODS: Expression and protein quantitative trait loci (eQTL and pQTL) datasets were analyzed to determine the causal relationships between gene/protein expression, and GC risk using MR and summary-data-based MR analyses. Mediation MR analysis, primarily based on the inverse-variance weighted (IVW) method, was applied to evaluate the potential mediating effects of 731 immune cells phenotypes. Sensitivity analyses were performed to validate the robustness and directionality of the findings. RESULTS: The analyses identified SARS2 and IL11RA as risk-promoting genes for GC, while PKN1 showed a protective association. Seven immune cell subsets were found to mediate the effects of these three genes on GC risk. In particular, SARS2-mediated CD8br and CD8dim% leukocytes, NKT%T cells, and CD45+CD4+ cells, which increased the risk of GC. CONCLUSION: SARS2, PKN1, and IL11RA genes mediate the risk-causal effects of GC through modulation of specific immune cell phenotypes.