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2742个背景基因显著富集的1558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。
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 2742 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.
作者
陈辉耀
董欣然
杨琳
卢宇蓝
胡黎园
蒋思远
钱莉玲
周文浩
CHEN Huiyao;DONG Xinran;YANG Lin;LU Yulan;HU Liyuan;JIANG Siyuan;QIAN Liling;ZHOU Wenhao(Institutes of Biomedical Sciences,Fudan University,Shanghai 201102,China;Center for Molecular Medicine,Children's Hospital of Fudan University,Shanghai 200032,China;Department of Pediatric Endocrinology and Inherited Metabolic Diseases,Children's Hospital of Fudan University,Shanghai 200032,China;Department of Neonatology,Children's Hospital of Fudan University,Shanghai 200032,China;Department of Respiratory Medicine,Children's Hospital of Fudan University,Shanghai 200032,China)
出处
《中国循证儿科杂志》
CSCD
北大核心
2022年第2期128-133,共6页
Chinese Journal of Evidence Based Pediatrics
基金
上海市科技重大专项:2017SHZDZX01
科技部国家重点研发计划:2020YFC2006402。
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
Bronchopulmonary dysplasia
Respiratory distress syndrome
Rare-variant association analysis