microRNAs与肺腺癌的因果关系：一项孟德尔随机化分析-现代医学

microRNAs与肺腺癌的因果关系：一项孟德尔随机化分析

单位：1. 川北医学院临床医学院, 四川南充 637000;
2. 川北医学院附属医院呼吸与危重症医学科, 四川南充 637000

分类号：R734.2

出版年·卷·期（页码）：2025·53·第四期（615-622）

摘要：

目的： 采用孟德尔随机化(MR)方法探究microRNAs与肺腺癌(LUAD)致病风险之间的因果关系。方法： 使用miR-eQTL数据和肺腺癌全基因组关联研究(GWAS)数据集，运用逆方差加权法(IVW)、MR Egger以及加权中位数法等3种孟德尔随机化方法，系统评估microRNAs与LUAD之间的因果关联。进行Cochran's Q检验、MR Egger截距检验、MR-PRESSO和留一法等敏感性分析，评估MR结果的稳健性。对IVW结果进行Meta分析，筛选更稳健的microRNAs，通过预测其靶基因和功能富集分析，解析致病microRNAs在肺腺癌中的潜在作用。结果： 筛选出3个重要microRNAs和LUAD存在因果关系，包括hsa-miR-27b-3p (OR=1.08,95%CI 1.03~1.13)、hsa-miR-130a-3p (OR=1.11,95%CI 1.08~1.14)和hsa-miR-196b-5p (OR=1.06,95%CI 1.02~1.10)。GO功能分析显示，致病microRNAs的预测靶点在细胞代谢、细胞生长等途径中显著富集，KEGG通路分析表明其在MAPK、TGF-β信号通路中显著富集。结论： 鉴定出3个关键microRNAs (hsa-miR-27b-3p、hsa-miR-130a-3p、和hsa-miR-196b-5p)，其表达调控可能在LUAD发生发展中发挥因果作用，这3个microRNAs的高表达是LUAD的危险因素。本研究提出的分析框架有助于理解microRNAs在LUAD发生发展中的作用，为临床应用提供了潜在的生物标志物。

Objective: To explore the causal relationship between microRNAs and the risk of lung adenocarcinoma(LUAD) using Mendelian randomization(MR). Methods: Utilizing miR-eQTL data and a genome-wide association study(GWAS) dataset for LUAD, Three MR methods—Inverse Variance Weighted(IVW), MR-Egger, and Weighted Median were applied to assess the causal associations between microRNAs and LUAD. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, MR-PRESSO and leave-one-out analysis were performed to validate the robustness of the MR results. A Meta-analysis of the IVW results was conducted to identify more robust microRNAs, and functional enrichment analysis was conducted to explore the potential roles of pathogenic microRNAs in lung adenocarcinoma by predicting their target genes. Results: Three microRNAs were significantly associated with LUAD risk: hsa-miR-27b-3p(OR=1.08, 95% CI 1.03-1.13), hsa-miR-130a-3p(OR=1.11, 95% CI 1.08-1.14), and hsa-miR-196b-5p(OR=1.06, 95% CI 1.02-1.10). Gene Ontology(GO) analysis revealed that the predicted targets of pathogenic microRNAs were significantly enriched in biological processes related to cell metabolism and growth. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis identified significant enrichment in the MAPK and TGF-β signaling pathways,which are critical in LUAD pathogenesis. Conclusion: Three key microRNAs(hsa-miR-27b-3p, hsa-miR-130a-3p, and hsa-miR-196b-5p) are identified, whose regulatory effects on gene expression may causally influence LUAD development. High expression levels of these microRNAs were associated with increased LUAD risk. The proposed analytical framework provides insights into the roles of microRNAs in LUAD pathogenesis and offers potential biomarkers for further research and clinical applications.

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