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中国循证儿科杂志

中国循证儿科杂志 ›› 2022, Vol. 17 ›› Issue (2): 128-133.

• 论著 • 上一篇    下一篇

新生儿呼吸窘迫综合征并发支气管肺发育不良风险基因巢式病例对照研究

陈辉耀1,2,董欣然2a,杨琳2b,卢宇蓝2a,胡黎园2c,蒋思远2c,钱莉玲2d,周文浩1,2   

  1. 1 复旦大学生物医学研究院上海，200032；2 复旦大学附属儿科医院上海，201102；a 分子医学中心，b 内分泌科，c 新生儿科，d 呼吸科
  • 收稿日期:2022-03-02 修回日期:2022-04-02 出版日期:2022-04-25 发布日期:2022-04-25
  • 通讯作者: 周文浩

Genetic factors for the risk of bronchopulmonary dysplasia in neonatal respiratory distress syndrome: A retrospective nested case-control study

CHEN Huiyao1,2, DONG Xinran2a, YANG Lin2b, LU Yulan2a, HU Liyuan2c, JIANG Siyuan2c, QIAN Liling2d, ZHOU Wenhao1,2   

  1. 1 Institutes of Biomedical Sciences, Fudan University, Shanghai 201102, China; 2 Children's Hospital of Fudan University, Shanghai 200032, China; a Center for Molecular Medicine, b Department of Pediatric Endocrinology and Inherited Metabolic Diseases, c Department of Neonatology, d Department of Respiratory Medicine
  • Received:2022-03-02 Revised:2022-04-02 Online:2022-04-25 Published:2022-04-25
  • Contact: ZHOU Wenhao, email: zhouwenhao@fudan.edu.cn

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摘要： 背景：既往已有许多针对支气管肺发育不良（BPD）风险基因的研究，但不同研究遗传表型差异大，无法作为呼吸窘迫综合征（RDS）并发BPD的遗传风险基因。 目的：筛选RDS并发BPD的遗传风险因素，明确其对RDS患儿预后的影响。 设计：巢式病例对照研究。 方法：以2016年1月1日至2021年8月1日在复旦大学附属儿科医院住院治疗、临床确诊RDS的患儿为队列人群，以是否并发BPD分为 BPD组和非BPD组。采用倾向性评分策略平衡2组胎龄，采用罕见变异关联性分析和功能富集分析，探索罕见变异基因富集的生物学过程，并筛选在BPD组中存在显著较多有害变异的候选风险基因。从GEO数据库检索RDS并发BPD高度相关基因表达数据，行基因表达模式的时间序列分析，验证本文高变异负荷基因的表达特征。 主要结局指标：RDS并发BPD风险基因。 结果：倾向性评分匹配后BPD组111例，非BPD组157例，2组的胎龄差异无统计学意义。基于2 742个背景基因显著富集的1 558个生物学过程（P<0.01），蛋白质截断变异最显著富集的基因集与蛋白激酶活性有关（P=0.011），BPD组中携带蛋白质截断变异的基因总数最多的是阳离子跨膜转运相关基因（P=0.027）。错义/非同义变异最显著富集的基因集与生长发育的调节有关（P=0.001）。BPD组中有26个基因的错义/非同义罕见变异负荷显著高于非BPD组（P<0.05），其中3个基因（ARSB、B9D2和UVSSA）差异有统计学意义（P<0.01）。通过GEO数据库数据验证，ARSB在重度BPD中显著低表达（P<0.001），时间序列分析发现ARSB基因在重度BPD新生儿中表达模式与无/轻度BPD新生儿差异有统计学意义（P<0.01）。 结论：ARSB基因为RDS并发BPD的风险基因。

关键词: 支气管肺发育不良, 呼吸窘迫综合征, 罕见变异关联分析

Abstract: Background：Many previous studies have been conducted on risk genes for bronchopulmonary dysplasia (BPD), but the phenotypic variation among studies is large, making it difficult to be used as a genetic risk for BPD in respiratory distress syndrome (RDS). Objective：To identify genetic risk factors for RDS complicated by BPD and to clarify the impact of genetic factors on the prognosis of children with RDS. Design：A retrospective nested casecontrol study. Methods：Children with clinically confirmed RDS who were hospitalized at the Children's Hospital of Fudan University from January 1, 2016, to August 1, 2021, were included and divided into BPD and nonBPD groups based on whether they had concomitant BPD. A propensity scoring strategy was used to balance the gestational age of the two groups, and rarevariant association analysis and functional enrichment analysis were used to explore the biological process of rare variant gene enrichment and to screen for candidate risk genes with significantly more damaging variants in the BPD group. Gene expression data were retrieved from the GEO database, and time series analysis of gene expression patterns was performed to verify the expression characteristics of the high variant burden genes in this paper. Main outcome measures：Genetic risk factors for RDS complicated by BPD. Results：There were 111 cases in the BPD group and 157 cases in the nonBPD group, and the differences of gestational age in the two groups were not statistically significant. Based on 1,558 biological processes of 2 742 significantly enriched background genes (P<0.01), the most significantly enriched gene set for proteintruncating variants was associated with regulation of protein kinase activity (P=0.011), and the largest total number of genes carrying proteintruncating variants in the BPD group was for cation transmembrane transportrelated genes (P=0.027). The set of most significantly enriched genes for missense or nonsynonymous variants was associated with the developmental growth (P=0.001). Twenty-six genes in the BPD group had a significantly higher burden of missense or nonsynonymous variants than that of the nonBPD group (P<0.05), with three genes (ARSB, B9D2 and UVSSA) having high statistical significance (P<0.01). ARSB was significantly downexpressed in severe BPD as verified by GEO database data (P<0.001), and time series analysis revealed a significantly different expression pattern of ARSB genes in neonates with severe BPD compared to neonates without BPD or with mild BPD (P<0.01). Conclusion：ARSB is a risk genetic factor for RDS complicated by BPD.

Key words: Bronchopulmonary dysplasia, Respiratory distress syndrome, Rare-variant association analysis