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中国循证儿科杂志

中国循证儿科杂志 ›› 2024, Vol. 19 ›› Issue (4): 294-301.DOI: 10.3969/j.issn.1673-5501.2024.04.006

• 论著 • 上一篇    下一篇

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

金禹汐1ab，李小雨2，刘一佳2，韩林利1ab，华益民1ab，范振鑫2，周开宇1ab，李星1ab，李一飞1ab
  

  1.  1 四川大学华西第二医院 成都，610041，a 出生缺陷与相关妇儿疾病教育部重点实验室，b 儿童心血管科；2 四川大学生命科学学院 成都，610041
  • 收稿日期:2024-06-21 修回日期:2024-08-15 出版日期:2024-08-25 发布日期:2024-10-31
  • 通讯作者: 李星；李一飞

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

JIN  Yuxi1ab, LI Xiaoyu2, LIU Yijia2, HAN Linli1ab, HUA Yimin1ab, FAN Zhenxin2, ZHOU Kaiyu1ab, LI Xing1ab, LI Yifei1ab   

  1. West China Second University Hospital, Sichuan University, Chengdu 610041, China, a. Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, b. Department of Pediatric Cardiology; 2 College of Life Sciences, Sichuan University, Chengdu 610041, China
  • Received:2024-06-21 Revised:2024-08-15 Online:2024-08-25 Published:2024-10-31
  • Contact: LI Xing; LI Yifei

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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609 732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<0.000 1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、PTGER1 15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、BRD2 6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抵抗的相关候选基因及SNP位点的研究价值还有待进一步探索。

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

Abstract: 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<0.000 1 as the threshold, fifteen candidate genes were associated with KD susceptibility, including MYT1L、CYP26B1、NECTIN3、TENM3、GFI1B、KNDC1、LOC100133315、RNF121、SYNE3、MAPKBP1、SLFN14、MYOM1、ABCA7、PIP5K1C、PTGER1(30 SNPs). While six candidate genes had been identified to be associated with coronary artery lesion, including DGKH、CCDC130、KLF7、METTL6、COLQ、PRKN(19 SNPs). Moreover, there were also six candidate genes had been recognized as risk factors with IVIG resistance, including MICALCL、NT5DC3、KRT75、LOC105370980、TXK、BRD2(8 SNPs). Conclusion：In this study,MYT1L（chr2, rs4381806）、NECTIN3（chr3, rs2399373）、MAPKBP1（chr15, rs2303517）have some significance in exploring the pathogenesis of KD. The SNP sites and genes asscociated with IVIG resistance and coronary artery lesions required further investigation.

Key words: Kawasaki disease, Coronary artery lesion, Ggenome-wide association study, High-throughput sequencing, Bioinformatics