Association of polymorphisms in C1orf106,IL1RN,and IL10 with post-induction infliximab trough level in Crohn’s disease patients  

克罗恩病患者C1orf106、IL1RN和IL10基因多态性与英夫利昔单抗诱导治疗后药物谷浓度的关系

作　　者：Jian Tang Cai-Bin Zhang Kun-Sheng Lyu Zhong-Ming Jin Shao-Xing Guan Na You Min Huang Xue-Ding Wang Xiang Gao 

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

出　　处：《Gastroenterology Report》2020年第5期367-373,I0002,共8页胃肠病学报道（英文）

基　　金：funded by grants from the National Natural Science Foundation of China[Grant No.81573507];the National Natural Science Foundation of China[Grant No.81473283];the National Natural Science Foundation of China[Grant No.81173131];the National Natural Science Foundation of China[Grant No.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,China[Grant No.2011A080300001].

摘　　要：Background:Trough levels of the post-induction serum infliximab(IFX)are associated with short-term and long-term responses of Crohn’s disease patients to IFX,but the inter-individual differences are large.We aimed to elucidate whether single gene polymorphisms(SNPs)within FCGR3A,ATG16L1,C1orf106,OSM,OSMR,NF-jB1,IL1RN,and IL10 partially account for these differences and employed a multivariate regression model to predict patients’post-induction IFX levels.Methods:The retrospective study included 189 Crohn’s disease patients undergoing IFX therapy.Post-induction IFX levels were measured and 41 tag SNPs within eight genes were genotyped.Associations between SNPs and IFX levels were analysed.Then,a multivariate logistic-regression model was developed to predict whether the patients’IFX levels achieved the threshold of therapy(3 lg/mL).Results:Six SNPs(rs7587051,rs143063741,rs442905,rs59457695,rs3213448,and rs3021094)were significantly associated with the post-induction IFX trough level(P=0.015,P<0.001,P=0.046,P=0.022,P=0.011,P=0.013,respectively).A multivariate prediction model of the IFX level was established by baseline albumin(P=0.002),rs442905(P=0.025),rs59457695(P=0.049),rs3213448(P=0.056),and rs3021094(P=0.047).The area under the receiver operating characteristic curve(AUROC)of this prediction model in a representative training dataset was 0.758.This result was verified in a representative testing dataset,with an AUROC of 0.733.Conclusions:Polymorphisms in C1orf106,IL1RN,and IL10 play an important role in the variability of IFX post-induction levels,as indicated in this multivariate prediction model of IFX levels with fair performance.背景:英夫利昔单抗(IFX)诱导治疗克罗恩病后的药物谷浓度会影响近、远期疗效,但药物谷浓度在个体间有很大差异。本研究旨在探究FCGR3A、ATG16L1、C1orf106、OSM、OSMR、NF-jB1、IL1RN及IL10等基因多态性是否与这种个体差异相关,并通过建立多因素回归模型来预测诱导治疗后IFX血药浓度。方法:回顾性纳入189例接受IFX治疗的克罗恩病患者。检测诱导治疗后IFX谷浓度和8个基因中41个标签单核甘酸多态性(tag SNP),分析二者之间的相关性。建立多因素逻辑回归模型来预测诱导治疗后的IFX浓度是否达到治疗剂量(3μg/mL)。结果:rs7587051(P=0.015)、rs143063741(P<0.001)、rs442905(P=0.046)、rs59457695(P=0.022)、rs3213448(P=0.011)和rs3021094(P=0.013)等6个SNP与诱导治疗后IFX谷浓度显著相关。IFX谷浓度的多因素预测模型纳入的变量包括:血浆白蛋白(P=0.002)、rs442905(P=0.025)、rs59457695(P=0.049)、rs3213448(P=0.056)和rs3021094(P=0.047)。该模型在训练队列中的受试者操作特征曲线下面积(AUROC)为0.758,在验证队列中的AUROC为0.733。结论:诱导治疗后IFX血药浓度的个体差异很大程度上是由C1orf106、IL1RN和IL10基因多态性所致,基于这些基因多态性的多因素预测模型可有效预测IFX血药浓度。

关 键 词：INFLIXIMAB inflammatory bowel disease single nucleotide polymorphism trough level multivariate prediction model 

分 类 号：R574[医药卫生—消化系统]