川崎病及其冠状动脉损伤和丙种球蛋白抵抗的病例对照研究  

Kawasaki disease,intravenous immunoglobulin resistance and coronary artery lesions:A case⁃control study

作　　者：金禹汐 李小雨 刘一佳 韩林利 华益民 范振鑫[3] 周开宇[1,2] 李星 李一飞[1,2] JIN Yuxi;LI Xiaoyu;LIU Yijia;HAN Linli;HUA Yimin;FAN Zhenxin;ZHOU Kaiyu;LI Xing;LI Yifei(West China Second University Hospital,Sichuan University,Chengdu 610041,China;Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects,College of Life Sciences,Sichuan University,Chengdu 610041,China;Department of Pediatric Cardiology,College of Life Sciences,Sichuan University,Chengdu 610041,China)

机构地区：[1]四川大学华西第二医院出生缺陷与相关妇儿疾病教育部重点实验室,成都610041 [2]四川大学华西第二医院儿童心血管科,成都610041 [3]四川大学生命科学学院,成都610041

出　　处：《中国循证儿科杂志》2024年第4期294-301,共8页Chinese Journal of Evidence Based Pediatrics

基　　金：国家自然科学基金:82270249。

摘　　要：背景川崎病(KD)的病因及预后的影响因素尚不明确,现有研究认为特殊基因背景下所导致的免疫反应是最终诱发KD免疫损伤并导致冠状动脉损伤的关键因素。目的探讨基因易感性在KD发病、冠状动脉损伤和IVIG抵抗中的意义。设计病例对照研究。方法依据美国心脏病协会指南诊断完全性KD,根据JCS/JSCS 2020指南以超声心动图冠状动脉内径Z值>2为标准定义冠状动脉损伤。完全性KD组纳入2020年4月至2022年1月于四川大学华西第二医院(我院)连续招募无血缘关系的完全性KD患儿;对照组纳入我院儿保科行健康体检并采集血标本的儿童。通过对两组行外周血标本基因组测序,原始数据质量控制、富集分析及位点注释,筛选与KD易感性、冠状动脉损伤和IVIG抵抗相关的单核苷酸多态性位点(SNP)及关联基因,比较KD的治疗反应及临床结局。主要结局指标KD及其冠状动脉损伤和IVIG抵抗相关基因及SNP。结果KD组177例,冠状动脉损伤32例(27%),IVIG抵抗55例(31%),对照组139例,两组年龄差异无统计学意义,性别和民族差异有统计学意义。通过上游分析,筛选了609732个SNP。2组以汉族和少数民族分类主成分分析呈现部分分离,性别分类的主成分分析不存在亚结构。以P<0.0001为阈值,在KD易感性的分析中共筛选出MYT1L、CYP26B1、NECTIN3、TENM3、GFI1B、KNDC1、LOC100133315、RNF121、SYNE3、MAPKBP1、SLFN14、MYOM1、ABCA7、PIP5K1C、PTGER115个候选基因(30个相关SNP位点),在冠状动脉损伤易感性的分析中共筛选出DGKH、CCDC130、KLF7、METTL6、COLQ、PRKN 6个候选基因(19个相关SNP位点),在IVIG抵抗的易感性分析中共筛选出MICALCL、NT5DC3、KRT75、LOC105370980、TXK、BRD26个候选基因(8个相关SNP位点)。结论KD易感性的分析中MYT1L(chr2,rs4381806)、NECTIN3(chr3,rs2399373)、MAPKBP1(chr15,rs2303517)对探讨KD发病机制有一定的研究价值,冠状动脉损伤和IVIG抵抗的相关候Background It is still unknown on the etiology,pathogenicity and associated prognostic factors of kawasaki disease(KD).Currently,multiple exposures which are collaborating with genetic background would induce the immunological responses and trigger the onset of KD,even coronary artery injuries.Objective To explore the significance of genetic susceptibility related to KD,IVIG resistance and coronary artery lesions.Design Case-control study.Methods Complete KD was diagnosed according to American Heart Association(AHA)guidelines,and coronary artery lesion was defined with echocardiography Z-score>2 according to the JCS/JSCS 2020 guidelines.From April 2020 to January 2022,we continuously recruited complete KD patients at West China Second University Hospital of Sichuan University.The children who were underwent physical examination and blood test from child health department in our hospital were enrolled in the controls.The whole exome sequencing of peripheral blood samples,quality control of raw data,enrichment analysis and site annotation were performed to screen for single nucleotide polymorphisms(SNPs)and associated genes related to KD,IVIG resistance and coronary artery lesions,which helped to compare the response to treatment and clinical outcomes of KD.Main outcome measures Sites of SNPs and genes which had been associated with KD,IVIG resistance and coronary artery lesions.Results In total,171 complete KD patients were enrolled,including 32 cases(27%)of coronary artery lesions and 55 cases(31%)of IVIG resistance,and 139 cases were enrolled in control group.There were no statistical differences in the age between two groups.A total of 609,732 SNPS were screened through upstream analysis.The two groups were separated by the principal component analysis categorized by Han and other ethic minorities,and there was no substructure in the principal component categorized by gender classification.With P<0.0001 as the threshold,fifteen candidate genes were associated with KD susceptibility,including MYT1L、CYP26B1、N

关 键 词：川崎病 冠状动脉损伤 基因组学 高通量测序 生物信息学 

分 类 号：R725.4[医药卫生—儿科]