The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University, Hangzhou, Zhejiang, 310006, China.
BMC Gastroenterol. 2024 Jun 14;24(1):197. doi: 10.1186/s12876-024-03284-x.
Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear.
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.
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.
This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.
先天/适应性免疫是抗肿瘤治疗的关键。然而，其与胃肠道（GI）癌症之间的因果关系尚不清楚。
从 MSigDB 数据库中提取免疫基因。将 GI 癌症的全基因组关联研究（GWAS）汇总数据与与基因相关的表达数量性状基因座（eQTL）和 DNA 甲基化数量性状基因座（mQTL）整合在一起。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 GI 癌症之间的因果关系。两样本 MR 分析用于敏感性分析。单细胞分析阐明了基因的富集情况。
三步 SMR 分析表明，一个假定的机制，即 cg17294865CpG 位点调节 HLA-DRA 表达，与胃癌风险呈负相关。HLA-DRA 在胃癌中的单核细胞/巨噬细胞和髓样细胞中表达差异显著。
本研究提供的证据表明，上调 HLA-DRA 的表达水平可以降低胃癌的风险。
