Mendelian randomization and bioinformatics analysis of TRIM31 with chronic liver disease

YOU Junyi; LIANG Guoqiang; SONG Xiudao

doi:10.12173/j.issn.1004-5511.202410153

Abstract：Objective Using two-sample Mendelian randomization(MR)to explore the causal relationship between the expression level of tripartite motif 31(TRIM31)in chronic liver disease,and using bioinformatics methods to analyze the role of TRIM31 in hepatocellular carcinoma(HCC).Methods The genetic data for non-alcoholic fatty liver disease(NAFLD),non-alcoholic steatohepatitis(NASH),liver fibrosis,cirrhosis,and HCC from the FinnGen R10,as well as the instrumental variables of single nucleotide polymorphisms(SNPs)significantly associated with TRIM31 expression in the cis eQTL data of GTEx Portal liver tissue were used for MR analysis,with the inverse-variance weighting as the main analysis method.The expression level of TRIM31 in HCC was analyzed using TCGA data,and the correlation between TRIM31 expression and immune cell infiltration was analyzed using the CIBERSORT algorithm.The diagnostic accuracy was evaluated by ROC curves.Differential gene expression analysis between high and low TRIM31 expression groups was performed using the TCGA database,and Gene Ontology(GO)enrichment,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment,and Gene Set Enrichment Analysis(GSEA)were conducted.Results The MR analysis results showed that the expression of TRIM31 in the liver was not significantly associated with NAFLD[OR=0.98,95%CI(0.91,1.05),P=0.515],NASH[OR=0.98,95%CI(0.74,1.29),P=0.868],liver fibrosis[OR=1.35,95%CI(0.84,2.17),P=0.218],and cirrhosis[OR=1.06,95%CI(0.95,1.17),P=0.292],but was significant associated with HCC[OR=1.26,95%CI(1.07,1.49),P=0.007].TCGA data analysis showed that compared with normal liver tissue,TRIM31 mRNA levels were significantly increased in HCC(P<0.001).ROC analysis showed that the area under the curve for TRIM31 in HCC diagnosis was 0.794[95%CI(0.738,0.851)].High TRIM31 expression was associated with increased immune scores and proportions of activated memory CD4+T cells,follicular helper T cells,regulatory T cells,while being inversely related to monocytes and M2 macrophages.GSEA analysis revealed that HCC samples with high TRIM31 expression were significantly enriched in signaling pathways closely associated with malignant progression,including the biological oxidation signaling pathway(FDR<0.05,NES=2.329)and calcium signaling pathway(FDR<0.05,NES=2.283).Conclusion Upregulated expression of liver TRIM31 may increase the risk of HCC,potentially through its regulation of the tumor immune microenvironment.These findings provide a theoretical basis for research into the pathogenesis of HCC.