Multi-alleles predict primary non-response to infliximab therapy in Crohn’s disease  

多等位基因预测英夫利昔单抗治疗克罗恩病的原发性无应答

作　　者：Cai-Bin Zhang Jian Tang Xue-Ding Wang Kun-Sheng Lyu Min Huang Xiang Gao 

机构地区：[1]Institute of Clinical Pharmacology,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [2]Department of Gastroenterology,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [3]Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [4]Southern China Center for Statistical Science School of Mathematics,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China

出　　处：《Gastroenterology Report》2021年第5期427-434,I0002,共9页胃肠病学报道（英文）

基　　金：supported by the National Natural Science Foundation of China[Grant No.81573507,81473283,81173131,and 81320108027];the Natural Major Projects for science and technology development from Science and Technology Ministry of China[Grant No.2012ZX09506001-004];the Major Scientific and Technological Project of Guangdong Province[Grant No.2011A080300001];the Medical Scientific Research Foundation of Guangdong Province of China[Grant No.A2020123].

摘　　要：Background:Infliximab(IFX)is the first-line treatment for patients with Crohn’s disease(CD)and is noted for its relatively high cost.The therapeutic efficacy of IFX has noticeable individual differences.Known single-gene polymorphisms(SNPs)are inadequate for predicting non-response to IFX.In this study,we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model.Methods:In this retrospective study,we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019.Primary non-response(PNR)and non-durable response(NDR)were evaluated using a simple endoscopic score for CD(SES-CD).A total of 125 SNPs within 44 genes were genotyped.A multivariate logistic-regression model was established to predict non-response to IFX.An area-under-the-receiver-operatingcharacteristics curve(AUROC)was applied to evaluate the predictive model performance.Results:Forty-two of 206(20.4%)patients experienced PNR and 15 of 159(9.4%)patients experienced NDR.Nine SNPs were associated with PNR(P<0.05).A PNR predictive model was established,incorporating 2-week high-sensitivity C-reactive protein(hs-CRP),rs61886887,rs61740234,rs357291,rs2269330,and rs111504845,and the AUROC on training and testing data sets were 0.818(P<0.001)and 0.888(P<0.001),respectively.At week 14,hs-CRP levels≥2.25 mg/L were significantly associated with NDR(AUROC=0.815,P<0.001).PNR-associated SNPs were not mutually associated with NDR,suggesting distinct mechanisms between PNR and NDR.Conclusion:Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.背景:英夫利昔单抗(IFX)是治疗克罗恩病的一线药物,价格昂贵。IFX的疗效具有显著的个体化差异,目前已知的单核苷酸多态性(SNP)预测IFX疗效效果欠佳。本研究旨在寻找与IFX治疗失败相关的新的遗传学标志物,并建立一个IFX原发性无应答的预测模型。方法:回顾性纳入接受IFX治疗的中国克罗恩病患者,采用克罗恩病简易内镜评分判定原发性无应答和继发性失应答。本研究总共检测了44个基因的125个SNP,建立基于SNP的多因素逻辑回归模型来预测IFX治疗无应答,并通过受试者工作特征曲线下面积(AUROC)来评价此模型的预测价值。结果:206例患者中,有42例(20.4%)患者对IFX原发性无应答;在159例接受IFX持续性治疗的患者中,有15例(9.4%)患者出现继发性失应答。在所检测的125个SNP中,有9个SNP与IFX原发性无应答相关(均P<0.05)。建立包括第2周超敏C反应蛋白(hs-CRP)、rs61886887、rs61740234、rs357291、rs2269330和rs111504845等指标的IFX原发性无应答预测模型,该模型在训练集中和测试集中的AUROC分别为0.818(P<0.001)和0.888(P<0.001)。此外,第14周hs-CRP≥2.25mg/L的患者继发性失应答的发生风险显著增高(AUROC=0.815,P<0.001)。而与IFX原发性无应答显著相关的9个SNP均与继发性失应答无关,说明IFX原发性无应答与继发性失应答之间的发生机制可能是不同的。结论:在中国克罗恩病患者中,单核苷酸多态性与IFX疗效显著相关。

关 键 词：INFLIXIMAB Crohn’s disease single nucleotide polymorphism therapeutic response 

分 类 号：R57[医药卫生—消化系统]