The relationship between innate/adaptive immunity and gastrointestinal cancer : a multi-omics Mendelian randomization study

TL;DR

This study explores how innate and adaptive immunity genes may influence gastrointestinal cancer risk, finding that higher HLA-DRA expression may lower gastric cancer risk.

Contribution

The novel contribution is identifying a causal link between HLA-DRA gene expression and reduced gastric cancer risk through multi-omics Mendelian randomization.

Findings

A CpG site regulating HLA-DRA expression is negatively associated with gastric cancer risk.

HLA-DRA is differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer.

Upregulating HLA-DRA may reduce gastric cancer risk.

Abstract

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.

The online version contains supplementary material available at 10.1186/s12876-024-03284-x.

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