Risk of gastric cancer in autoimmune gastritis and pernicious anaemia: Insights from Mendelian randomization and multi‐omics analysis

Abstract Background The newly onset debate surrounding the risk of gastric cancer (GC) in autoimmune gastritis (AIG) and pernicious anaemia has intensified. It is necessary to supplement higher level research evidences to settle this issue. Methods Two‐sample Mendelian randomization (MR) analysis using inverse variance weighted method was conducted to reveal the causal relationship between pernicious anaemia and GC. Because of the absence of available summary statistics for AIG at present, we used pernicious anaemia as a proxy exposure, as it was frequently used interchangeably. The multi‐omics characteristics of AIG and pernicious anaemia were further explored through proteome‐wide MR, colocalization, and transcriptome sequencing analysis. Results MR analysis found pernicious anaemia was causally associated with a higher risk of GC (odds ratio: 1.16, 95% confidence interval [1.03, 1.31], p = .018). Sensitivity analyses confirmed the stability of the results. The up‐regulation of genes involved in gastric dysplasia and carcinogenesis, including receptor activity‐modifying protein 3, fibroblast growth factor 3, transforming growth factor beta‐2 and tumour‐associated calcium signal transducer 2, suggested potential mechanisms underlying the risk of GC in AIG. Conclusions These results emphasized the independent link from AIG and pernicious anaemia to GC. Therefore, endoscopy follow‐up for GC screening in AIG is still appealed.