综合基因组分析确定细胞间粘附分子1在儿童哮喘中的作用。

Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma.

作者信息

Klaassen Ester M M, van de Kant Kim D G, Jöbsis Quirijn, Penders John, van Schooten Frederik Jan, Quaak Marieke, den Hartog Gertjan J M, Koppelman Gerard H, van Schayck Constant P, van Eys Guillaume, Dompeling Edward

机构信息

Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands.

出版信息

Pediatr Allergy Immunol. 2014 Mar;25(2):166-72. doi: 10.1111/pai.12187. Epub 2014 Jan 6.

DOI:10.1111/pai.12187

PMID:24393359

Abstract

BACKGROUND

Childhood asthma is characterized by chronic airway inflammation. Integrative genomic analysis of airway inflammation on genetic and protein level may help to unravel mechanisms of childhood asthma. We aimed to employ an integrative genomic approach investigating inflammation markers on DNA, mRNA, and protein level at preschool age in relationship to asthma development.

METHODS

In a prospective study, 252 preschool children (202 recurrent wheezers, 50 controls) from the Asthma DEtection and Monitoring (ADEM) study were followed until the age of six. Genetic variants, mRNA expression in peripheral blood mononuclear cells, and protein levels in exhaled breath condensate for intercellular adhesion molecule 1 (ICAM1), interleukin (IL)4, IL8, IL10, IL13, and tumor necrosis factor α were analyzed at preschool age. At six years of age, a classification (healthy, transient wheeze, or asthma) was based on symptoms, lung function, and medication use.

RESULTS

The ICAM1 rs5498 A allele was positively associated with asthma development (p = 0.02) and ICAM1 gene expression (p = 0.01). ICAM1 gene expression was positively associated with exhaled levels of soluble ICAM1 (p = 0.04) which in turn was positively associated with asthma development (p = 0.01). Furthermore, rs1800872 and rs1800896 in IL10 were associated with altered IL10 mRNA expression (p < 0.01). Exhaled levels of IL4, IL10, and IL13 were positively associated with asthma development (p < 0.01).

CONCLUSIONS

In this unique prospective study, we demonstrated that ICAM1 is associated with asthma development on DNA, mRNA, and protein level. Thus, ICAM1 is likely to be involved in the development of childhood asthma.

摘要

背景

儿童哮喘的特征是慢性气道炎症。在基因和蛋白质水平上对气道炎症进行综合基因组分析可能有助于揭示儿童哮喘的发病机制。我们旨在采用综合基因组方法，研究学龄前儿童DNA、mRNA和蛋白质水平上的炎症标志物与哮喘发展的关系。

方法

在一项前瞻性研究中，对哮喘检测与监测（ADEM）研究中的252名学龄前儿童（202名反复喘息儿童，50名对照）进行随访至6岁。在学龄前分析细胞间黏附分子1（ICAM1）、白细胞介素（IL）4、IL8、IL10、IL13和肿瘤坏死因子α的基因变异、外周血单核细胞中的mRNA表达以及呼出气冷凝物中的蛋白质水平。6岁时，根据症状、肺功能和用药情况进行分类（健康、短暂喘息或哮喘）。

结果

ICAM1 rs5498 A等位基因与哮喘发展呈正相关（p = 0.02）和ICAM1基因表达呈正相关（p = 0.01）。ICAM1基因表达与可溶性ICAM1的呼出水平呈正相关（p = 0.04），而可溶性ICAM1的呼出水平又与哮喘发展呈正相关（p = 0.01）。此外，IL10中的rs1800872和rs1800896与IL10 mRNA表达改变有关（p < 0.01）。IL4、IL10和IL13的呼出水平与哮喘发展呈正相关（p < 0.01）。