血浆SPARC介导的外周血嗜酸性粒细胞在胃癌中的作用:基于多变量孟德尔随机化研究和中介分析  

Role of Circulating Eosinophils Mediated by Plasma SPARC in Gastric Cancer:A Multivariable Mendelian Randomization Study and Mediation Analysis

作　　者：韩政轩 杨朝纲[1,2] 熊浩 熊斌 HAN Zhengxuan;YANG Chaogang;XIONG Hao;XIONG Bin(Department of Gastrointestinal Surgery,Zhongnan Hospital of Wuhan University,Wuhan,430071,China;Hubei Key Laboratory of Tumor Biological Behaviors&Hubei Cancer Clinical Study Center,Wuhan,430071,China;Information Center,Zhongnan Hospital of Wuhan University,Wuhan,430071,China)

机构地区：[1]武汉大学中南医院胃肠外科,武汉市430071 [2]肿瘤生物学行为湖北省重点实验室&湖北省肿瘤医学临床研究中心,武汉市430071 [3]武汉大学中南医院信息中心,武汉市430071

出　　处：《医学分子生物学杂志》2024年第2期100-107,共8页Journal of Medical Molecular Biology

基　　金：国家自然科学基金(No.82372979);中央高校基本科研业务费专项资金(No.2042021kf0143);湖北省自然科学基金(No.2021CFB100)。

摘　　要：目的外周血免疫细胞计数与胃癌的发生发展以及胃癌患者的预后之间的联系往往易受到反向因果关系和混杂因素的影响,研究旨在运用孟德尔随机化分析排除相关偏倚,阐明外周免疫细胞计数和胃癌的因果关系。方法主要采用单因素和多因素孟德尔随机化的方法,利用全基因组关联研究(genomewide association study,GWAS)数据,探究外周血中各免疫细胞亚型与胃癌发生风险之间的因果关系。将白细胞、粒细胞、中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、淋巴细胞、单核细胞计数作为暴露因素,选用逆方差加权法作为单变量孟德尔随机化分析的主要方法。随后进行了两步法中介分析,探究血浆蛋白可能起到的作用。结果淋巴细胞(OR=1.094,95%CI:1.009~1.185,P=0.029)、嗜酸性粒细胞(OR=0.881,95%CI:0.813~0.955,P=0.002)与胃癌之间存在因果关系,敏感性分析进一步证实了此结果的可靠性。而嗜酸性粒细胞降低胃癌发生风险之间的关联在多变量孟德尔随机化分析中仍然显著(OR=0.807,95%CI:0.671~0.970,P=0.023),反向因果关系不显著。酸性富含半胱氨酸分泌蛋白(secreted protein acidic and rich in cysteine,SPARC)是一种细胞外基质蛋白,参与多种细胞-基质相互作用和细胞信号转导途径,在肿瘤发展中发挥重要作用。对1124种血浆蛋白进行中介分析,结果提示血浆SPARC可能介导了嗜酸性粒细胞对胃癌的保护作用(Beta=-0.030,95%CI:-0.072~0.000,P=0.024)。结论孟德尔随机化分析证明嗜酸性粒细胞计数是降低胃癌发病率的独立因素,血浆SPARC在此过程中起中介作用,外周嗜酸性粒细胞计数和外周血SPARC有潜力成为胃癌发生的早期临床指标和治疗靶点,孟德尔随机化的方法还有效地避免了反向因果关系和社会心理等因素造成的偏倚,但是未来仍需要更多的研究来证明其内部的生物学机制。Objective East Asia exhibits one of the highest global incidence rates of gastric cancer.The intricate relationship between peripheral blood immune cell counts and the onset and progression of gastric cancer is often obscured by reverse causality and confounders.This study employs Mendelian randomization analysis to mitigate associated biases,aiming to elucidate the causal connection between peripheral immune cell counts and gastric cancer.Methods Both univariate and multivariate Mendelian randomization methods were employed to explore the causal relationship between diverse immune cell subtypes in peripheral blood and the risk of gastric cancer using data from Genome-wide association studies(GWAS).Exposure factors included counts of white blood cells,granulocytes,neutrophils,eosinophils,basophils,lymphocytes,and monocytes.The primary approach for univariate Mendelian randomization analysis involved the inverse variance-weighted method.Afterwards,a two-step mediation analysis was conducted to investigate the potential role of plasma proteins in this process.Results Mendelian randomization analysis revealed a causal relationship between lymphocytes(OR=1.094,95%CI:1.009-1.185,P=0.029)and eosinophils(OR=0.881,95%CI:0.813-0.955,P=0.002)and the incidence of gastric cancer.Sensitivity analysis corroborated the reliability of these results.Furthermore,the association between decreased eosinophil counts and a reduced risk of gastric cancer persisted in multivariate Mendelian randomization analysis(OR=0.807,95%CI:0.671-0.970,P=0.023).Reverse causality was not significant.The secreted protein acidic and rich in cysteine(SPARC)is an extracellular matrix protein that involves in various cell-matrix interactions and cellular signaling pathways,playing a significant role in tumor development.The mediation analysis of 1124 plasma proteins suggested that plasma SPARC might mediate the protective effect of eosinophils against gastric cancer(Beta=-0.030,95%CI:-0.072-0.000,P=0.024).Conclusion Mendelian randomization analysis establ

关 键 词：孟德尔随机化 胃癌 免疫细胞 嗜酸性粒细胞 淋巴细胞 

分 类 号：R735.2[医药卫生—肿瘤]