Mendelian randomization analysis and molecular mechanism of T-cell exhaustion-related genes in multiple myeloma
- VernacularTitle:多发性骨髓瘤T细胞耗竭相关基因的孟德尔随机化分析及分子机制研究
- Author:
Ziying YU
1
;
Luyan HU
;
Yangmin ZHU
;
Zhao YIN
;
Zhi LIU
;
Ruiming OU
Author Information
- Keywords: T-cell exhaustion; Mendelian randomization; multiple myeloma; prognosis; PR/SET domain 1; ectonucleoside triphosphate diphosphohydrolase 1; protein tyrosine phosphatase non-receptor type 11; major histocompatibility complex,class Ⅰ,B
- From: Journal of Clinical Medicine in Practice 2025;29(19):41-52
- CountryChina
- Language:Chinese
- Abstract: Objective To investigate the expression changes of T-cell exhaustion-related genes in multiple myeloma(MM)and their potential causal relationships.Methods A bidirectional summary-level Mendelian randomization(MR)analysis was used to explore the causal relationship between T-cell exhaustion and MM.The eQTL data and genome-wide association study(GWAS)were used to summarize data,and corresponding single nucleotide polymorphisms(SNPs)were extracted as instru-mental variables.Four methods,namely inverse variance weighted(IVW)method,MR Egger,weighted median,and weighted mode were used to assess the reliability of the causal relationship.The robustness of the results was validated using Cochran's Q heterogeneity test and pleiotropy test.In cel-lular models,RNA interference was used to silence key target genes,and phenotypic changes such as myeloma cell viability,colony-forming ability,and apoptosis were observed to experimentally confirm the causal effects revealed by MR.Results The genes PRDM1,ENTPD1,PTPN11,and HLA-B were involved in the T-cell exhaustion process in MM.The presence of the PRDM1 gene(OR=0.998 5,95％CI,0.997 1 to 0.999 8,P=0.024 6)may reduce the risk of MM,whereas ENTPD1(OR=1.000 4,95％CI,1.000 1 to 1.000 7,P=0.015 8),HLA-B(OR=1.000 4,95％CI,1.000 1 to 1.000 8,P=0.012 4),and PTPN11(OR=1.002 5,95％CI,1.001 0 to 1.003 9,P=0.001 2)were associated with an increased risk of MM.Real-time quantitative polymerase chain reaction showed overexpression of PTPN11 in MM cell lines and patients' samples.By assessing cell viabili-ty,colony formation and detecting apoptosis,it was found that inhibiting PTPN11 promoted apopto-sis in MM cell lines.Conclusion A causal relationship exists between T-cell exhaustion and MM.Targeted interventions against specific T-cell exhaustion-related genes may help reduce the incidence of MM.
