Katayama Shintaro, Stenberg Hammar Katarina, Krjutškov Kaarel, Einarsdottir Elisabet, Hedlin Gunilla, Kere Juha, Söderhäll Cilla
Dept of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Both authors contributed equally.
Eur Respir J. 2020 Jan 23;55(1). doi: 10.1183/13993003.01330-2019. Print 2020 Jan.
Airway obstruction and wheezing in preschool children with recurrent viral infections are a major clinical problem, and are recognised as a risk factor for the development of chronic asthma. We aimed to analyse whether gene expression profiling provides evidence for pathways that delineate distinct groups of children with wheeze, and in combination with clinical information could contribute to diagnosis and prognosis of disease development.
We analysed leukocyte transcriptomes from preschool children (6 months-3 years) at acute wheeze (n=107), and at a revisit 2-3 months later, comparing them to age-matched healthy controls (n=66). RNA-sequencing applying GlobinLock was used. The cases were followed clinically until age 7 years. Differential expression tests, weighted correlation network analysis and logistic regression were applied and correlations to 76 clinical traits evaluated.
Significant enrichment of genes involved in the innate immune responses was observed in children with wheeze. We identified a unique acute wheeze-specific gene-module, which was associated with vitamin D levels (p<0.005) in infancy, and asthma medication and FEV%/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio several years later, at age 7 years (p<0.005). A model that predicts leukotriene receptor antagonist medication at 7 years of age with high accuracy was developed (area under the curve 0.815, 95% CI 0.668-0.962).
Gene expression profiles in blood from preschool wheezers predict asthma symptoms at school age, and therefore serve as biomarkers. The acute wheeze-specific gene module suggests that molecular phenotyping in combination with clinical information already at an early episode of wheeze may help to distinguish children who will outgrow their wheeze from those who will develop chronic asthma.
反复病毒感染的学龄前儿童出现气道阻塞和喘息是一个主要的临床问题，并且被认为是慢性哮喘发生的一个危险因素。我们旨在分析基因表达谱是否能为区分不同喘息儿童群体的途径提供证据，以及与临床信息相结合是否有助于疾病发展的诊断和预后评估。
我们分析了学龄前儿童（6个月至3岁）在急性喘息期（n = 107）以及2至3个月后复诊时的白细胞转录组，并将其与年龄匹配的健康对照（n = 66）进行比较。采用应用GlobinLock的RNA测序技术。对这些病例进行临床随访至7岁。应用差异表达测试、加权相关网络分析和逻辑回归，并评估与76种临床特征的相关性。
在喘息儿童中观察到参与固有免疫反应的基因显著富集。我们鉴定出一个独特的急性喘息特异性基因模块，其与婴儿期的维生素D水平（p < 0.005）以及数年后7岁时的哮喘药物治疗和FEV%/FVC（1秒用力呼气量/用力肺活量）比值相关（p < 0.005）。开发了一个能高精度预测7岁时白三烯受体拮抗剂药物治疗情况的模型（曲线下面积为0.815，95%可信区间为0.668 - 0.962）。
学龄前喘息儿童血液中的基因表达谱可预测学龄期哮喘症状，因此可作为生物标志物。急性喘息特异性基因模块表明，在喘息早期将分子表型与临床信息相结合可能有助于区分喘息会自愈的儿童和会发展为慢性哮喘的儿童。
