背景：固有/适应性免疫是抗肿瘤治疗的关键。然而,其与胃肠道（GI）癌症的因果关系尚不清楚。
方法：从MSigDB数据库中提取免疫基因。将GI癌的全基因组关联研究（GWAS）摘要数据与与基因相关的表达定量性状基因座（eQTL）和DNA甲基化定量性状基因座（mQTL）进行整合。基于汇总数据的孟德尔随机化（SMR）和共定位分析用于揭示基因与胃肠道癌症之间的因果关系。敏感性分析采用双样本MR分析。单细胞分析阐明了基因的富集。
结果：三步SMR分析表明，一种假定的机制，cg17294865CpG位点调控HLA-DRA表达与胃癌风险呈负相关。HLA-DRA在胃癌中的单核细胞/巨噬细胞和骨髓细胞中的表达显着差异。
结论：这项研究提供了证据，表明上调HLA-DRA的表达水平可以降低胃癌的风险。
BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear.
METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes.
RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer.
CONCLUSIONS: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.
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