双向孟德尔随机化分析免疫细胞表型与复发性阿弗他溃疡之间的因果关系  

Bidirectional Mendelian randomization analysis of causal relationships between immune cell traits and recur⁃rent aphthous ulceration

作　　者：谢雪洁 徐隽[1,2] 刘媛 陈悦 唐莉[1,2] 古丽努尔·阿吾提[1,2] XIE Xuejie;XU Jun;LIU Yuan;CHEN Yue;TANG Li;GULINUER Awuti(Department of Periodontal and Mucosal,the First Affiliated Hospital of Xinjiang Medical University(the Affiliated Stomatology Hospital of Xinjiang Medical University),Urumqi 830054,China;Stomatology Disease Institute of Xinjiang Uyghur Autonomous Region,Urumqi 830054,China;Department of Endodontics,the First Affiliated Hospital of Xinjiang Medical University(the Affiliated Stomatology Hospital of Xinjiang Medical University),Urumqi 830054,China)

机构地区：[1]新疆医科大学第一附属医院(附属口腔医院)牙周黏膜科,新疆维吾尔自治区乌鲁木齐830054 [2]新疆维吾尔自治区口腔医学研究所,新疆维吾尔自治区乌鲁木齐830054 [3]新疆医科大学第一附属医院(附属口腔医院)牙体牙髓病科,新疆维吾尔自治区乌鲁木齐830054

出　　处：《口腔疾病防治》2025年第4期296-304,共9页Journal of Prevention and Treatment for Stomatological Diseases

基　　金：新疆维吾尔自治区青年科学基金(2022D01C253)。

摘　　要：目的 利用孟德尔随机化(Mendelian randomization,MR)探索731种免疫细胞表型与复发性阿弗他溃疡(recurrent aphthous ulcer,RAU)之间的双向因果关系。方法 利用公开发布的731种免疫细胞表型的全基因组关联研究(genome-wide association studies,GWAS)统计数据与来自FinnGen联盟RAU的GWAS统计数据进行了两样本双向MR研究。逆方差加权法(inverse variance weighted,IVW)作为主要的分析方法,加权中位数法(weighted median,WM)、MR-Egger回归、加权众数法以及简单众数法作为补充性的分析工具。敏感性分析则依赖于Cochran's Q检验、孟德尔随机化多效性残差与异常值识别法(mendelian randomization pleiotropy residual sum and outlier,MR-PRESSO)以及留一交叉验证法(leave-one-out approach)。此外,利用来源于基因表达综合数据库(Gene Expression Omnibus,GEO)的一项临床队列数据集进行差异性分析,进一步辅助验证MR结果。结果 在正向MR分析中,731种免疫表型作为暴露因素,RAU作为结局,其中有52个免疫细胞表型对RAU的因果效应显著(P<0.05),经过假阳性发现率(false discovery rate,FDR)校正后,发现2个免疫表型与RAU风险显著相关:随着单核髓源性抑制细胞(monocytic myeloid-derived suppressor cells,M-MDSC)(OR=1.06,95%CI:1.03-1.09)以及粒细胞髓源性抑制细胞(granulocytic myeloid-derived suppressor cells,G-MDSC)上的CD33分子(OR=1.06,95%CI:1.03-1.09)的增加,RAU的风险也随之增加。反向MR中,RAU对2个免疫细胞表型因果效应显著(P<0.05),但经FDR矫正后,未发现有显著效应的免疫细胞表型。敏感性分析结果显示:所有SNPs之间并未展现出显著的异质性(P>0.05)。GEO数据集差异性分析结果显示:髓源性抑制细胞(myeloid-derived suppressor cells,MDSC)的特征基因(CTBS、IPMK及UBA3)在RAU中表达升高,差异具有统计学意义(P<0.05)。结论 731种免疫细胞中的M-MDSC与G-MDSC上的CD33分子可能是RAU发生的危险因素,RAU的临床GEO数据�Objective To explore the bidirectional causal relationship between 731 immune cell phenotypes and recurrent aphthous ulcers(RAU)using Mendelian randomization(MR).Methods A two-sample bidirectional MR study was conducted using publicly available genome-wide association study(GWAS)summary statistics for 731 immune cell phenotypes and the RAU GWAS summary data from the FinnGen consortium.The inverse-variance weighted(IVW)method was used as the primary analysis tool,with supplementary analyses including the weighted median(WM)method,MR-Egger regression,weighted mode,and simple mode.Sensitivity analyses were conducted using Cochran’s Q test,the mendelian randomization pleiotropy residual sum and outlier(MR-PRESSO)method for detecting pleiotropy and outliers,and leave-one-out cross-validation.Furthermore,differential analysis was performed using a clinical cohort dataset from the Gene Expression Omnibus(GEO)to further validate the MR results.Results In the forward MR analysis,731 immune cell phenotypes were considered as exposures and RAU as the outcome.Among them,52 immune cell phenotypes showed a significant causal effect on RAU(P<0.05).After false discovery rate(FDR)correction,two immune phenotypes remained significantly associated with RAU risk:with increased monocyte-derived myeloid suppressor cells(M-MDSC)(OR=1.06;95%CI:1.03-1.09)and CD33 on granulocytic myeloid-derived suppressor cells(G-MDSC)(OR=1.06;95%CI:1.03-1.09),the risk of RAU also increased.In reverse MR,RAU was found to have a significant causal effect on two immune cell phenotypes(P<0.05),but no significant effects were found after FDR correction.Sensitivity analysis showed no significant heterogeneity between SNPs(P>0.05).Differential analysis of the GEO dataset revealed that the characteristic genes of myeloid-derived suppressor cells(MDSC)(CTBS,IPMK,and UBA3)were significantly upregulated in RAU(P<0.05).Conclusion The MR results of 731 immune cell phenotypes suggest that M-MDSC and CD33 molecules on G-MDSC may be risk factors for RAU development.T

关 键 词：免疫表型 复发性阿弗他溃疡 因果推断 孟德尔随机化 髓源性抑制细胞 单核髓源性抑制细胞 粒细胞髓源性抑制细胞 单核苷酸多态性 基因组关联研究 

分 类 号：R78[医药卫生—口腔医学]