肿瘤坏死因子相关凋亡诱导配体基因多态性及其血浆表型与克罗恩病的关系  

Tumor necrosis factor-related apoptosis-inducing ligand gene polymorphism and its plasma phenotype in relation to Crohn′s disease

作　　者：朱浩奇 胡平 徐芳[1] 邵晓晓[1] 曹曙光[1] 吴昊[1] 蒋益[1] Zhu Haoqi;Hu Ping;Xu Fang;Shao Xiaoxiao;Cao Shuguang;Wu Hao;Jiang Yi(Department of Gastroenterology,the Second Affiliated Hospital of Wenzhou Medical University,Wenzhou 325000,China)

机构地区：[1]温州医科大学附属第二医院育英儿童医院消化内科,温州325000

出　　处：《中华医学杂志》2023年第8期585-593,共9页National Medical Journal of China

基　　金：浙江省自然科学基金(LY18H030009);浙江省医药卫生科技计划项目(2021KY802、2021KY803);浙江省中医药科技计划项目(2019ZB075);温州市科技计划项目(Y20190603);贺林院士工作站科研基金(19331101)

摘　　要：目的探讨肿瘤坏死因子相关凋亡诱导配体(TRAIL)基因多态性及血浆可溶性TRAIL(sTRAIL)水平与克罗恩病(CD)的关系,并回顾性分析TRAIL基因变异及血浆sTRAIL水平对英夫利昔单抗(IFX)临床应答的影响。方法2012年1月至2021年1月,从温州医科大学附属第二医院消化内科收集312例CD患者[男205例,女107例,年龄(33.9±9.8)岁]和514名性别、年龄相匹配的正常对照者[男304名,女210名,年龄(34.9±9.4)岁]。患者中72例对传统药物治疗无效或不耐受的活动期CD患者接受IFX(5 mg/kg)规范治疗,第14周时依据Harvey-Bradshaw指数(HBI)和CD简化内镜评分(SES-CD)的变化分为应答组[HBI下降≥3分和(或)SES-CD下降≥50%]和无应答组。采用基质辅助激光解吸电离-飞行时间质谱技术检测TRAIL(rs1131568)基因多态性,酶联免疫吸附法检测血浆sTRAIL水平。依据“蒙特利尔CD表型分类标准”将患者分层(确诊年龄、疾病部位、疾病行为)。全面分析rs1131568基因多态性和血浆sTRAIL水平与CD发病风险、临床病理特征及IFX临床应答的关系。结果隐性模型分析显示,中重度活动期CD患者中rs1131568纯合子变异基因型(CC)的频率高于轻度活动期CD患者(45.34%比29.23%,P=0.005)。(狭窄型+穿透型)CD患者中rs1131568变异等位基因(C)和纯合子变异基因型(CC)的频率均高于非狭窄非穿透型CD患者(65.48%比57.53%,P=0.046;49.21%比31.18%,P=0.001)。显性模型分析发现,合并肛周病变的CD患者中变异等位基因(C)和变异基因型(TC+CC)的频率均高于无肛周病变的CD患者(66.83%比58.17%,P=0.037;92.31%比78.37%,P=0.002)。CD组中血浆sTRAIL平均水平高于正常对照组[(243.04±42.74)ng/L比(194.16±31.14)ng/L,P<0.001]。中重度活动期CD患者中血浆sTRAIL水平高于轻度活动期CD患者[263.47(242.09,281.91)ng/L比231.13(211.11,247.11)ng/L,P<0.001]。(狭窄型+穿透型)CD患者中血浆sTRAIL水平高于非狭窄非穿透型CD患者[266.18(246.68,289.91)ng/L比Objectives To investigate the associations of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)gene polymorphism and plasma soluble TRAIL level(sTRAIL)with Crohn′s disease(CD)and to retrospectively analyze the effects of TRAIL gene variants and plasma sTRAIL levels on clinical response to infliximab(IFX).Methods From January 2012 to January 2021,312 CD patients[205 males,107 females,average age(33.9±9.8)years]and 514 age-and gender-matched healthy controls[304 males,210 females,average age(34.9±9.4)years]were recruited from the Department of Gastroenterology,the Second Affiliated Hospital of Wenzhou Medical University.Among them,72 patients with active CD who were ineffective or intolerant to traditional drug therapy regularly received IFX(5 mg/kg)treatment.According to the changes in the Harvey-Bradshaw index(HBI)and the Simplified Endoscopic Score for Crohn′s Disease(SES-CD)in the 14^(th)week,these patients were classified into response group(a decrease in HBI≥3 or a decrease in SES-CD≥50%)and non-response group.TRAIL(rs1131568)gene polymorphism was analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry technique.The plasma sTRAIL level was examined by enzyme-linked immunosorbent assay(ELISA).Based on the Montreal CD classification criteria,all CD patients were divided into different subgroups.Finally,a comprehensive analysis was performed to investigate the relationship between TRAIL(rs1131568)gene polymorphism,the plasma sTRAIL level and the risk of CD,the clinicopathological characteristics of CD patients,and the clinical response to IFX.Results The recessive model analysis showed that the homozygous variant genotype(CC)was more prevalent in patients with moderately to severely active CD than in those with mildly active CD(45.34%vs 29.23%,P=0.005).Both variant allele(C)and homozygous variant genotype(CC)in patients with stricturing and penetrating CD were more frequent than those in patients with non-stricturing and non-penetrating CD(65.48%vs 57.53%,P

关 键 词：克罗恩病 肿瘤坏死因子相关凋亡诱导配体 基因多态性 可溶性TRAIL 英夫利昔单抗 

分 类 号：R574.62[医药卫生—消化系统]