Abstract

Numerous studies have suggested a possible link between inflammatory cytokines and gastric malignancies; however, the causal relationships remain ambiguous. To address this uncertainty, the present study utilized Mendelian randomization (MR) to investigate the causal effects of inflammatory cytokine levels on the development of malignant gastric neoplasms. Genetic variation datasets for 91 inflammatory cytokines were collected from genome-wide association studies (GWASs), and information on malignant neoplasms of the stomach was obtained from the Finnish database. The primary analysis was carried out via the inverse variance weighted (IVW) method. To evaluate the robustness and validity of the causal inferences, pleiotropy residual sum and outlier tests, MR-Egger intercepts, Cochran's Q tests, and leave-one-out analyses were conducted. Additionally, we utilized reverse MR to examine the possibility of reverse causation. The IVW results indicated that the levels of interleukin-10 receptor subunit beta (IL-10RA) (OR = 1.1468; 95% CI: 1.0064-1.3068; P = 0.0398) and the levels of tumor necrosis factor ligand superfamily member 14 (OR = 1.1693; 95% CI: 1.0016-1.3651; P = 0.0476) increased the likelihood of a high risk of malignant neoplasm of the stomach, whereas matrix metalloproteinase-1 (MMP-1) had a protective effect on the malignant neoplasm of the stomach (OR = 0.7813; 95% CI: 0.6125-0.9968; P = 0.0471). IL-10RA and MMP-1 were also validated in a subset of adenocarcinomas and papillary adenocarcinomas of the stomach. TNFSF14 and PD-L1 revealed positive evidence to support causality with malignant neoplasms of the stomach and adenocarcinoma, respectively. This study reveals potential associations between 91 inflammatory cytokines and the risk of malignant gastric neoplasms, as indicated by MR analysis. These findings provide important insights that may facilitate the development of diagnostic biomarkers and aid in the identification of novel therapeutic targets for gastric cancer.

Keywords

inflammatory cytokines, gastric malignant neoplasm, gastric adenocarcinoma, MR