An <i>ADAM33</i> Polymorphism Associates with Progression of Preschool Wheeze into Childhood Asthma: A Prospective Case-Control Study with Replication in a Birth Cohort Study

Background
The influence of asthma candidate genes on the development from wheeze to asthma in young children still needs to be defined.
Objective
To link genetic variants in asthma candidate genes to progression of wheeze to persistent wheeze into childhood asthma.
Materials and Methods
In a prospective study, children with recurrent wheeze from the ADEM (Asthma DEtection and Monitoring) study were followed until the age of six. At that age a classification (transient wheeze or asthma) was based on symptoms, lung function and medication use. In 198 children the relationship between this classification and 30 polymorphisms in 16 asthma candidate genes was assessed by logistic regression. In case of an association based on a p<0.10, replication analysis was performed in an independent birth cohort study (KOALA study, n = 248 included for the present analysis).
Results
In the ADEM study, the minor alleles of ADAM33 rs511898 and rs528557 and the ORMDL3/GSDMB rs7216389 polymorphisms were negatively associated, whereas the minor alleles of IL4 rs2243250 and rs2070874 polymorphisms were positively associated with childhood asthma. When replicated in the KOALA study, ADAM33 rs528557 showed a negative association of the CG/GG-genotype with progression of recurrent wheeze into childhood asthma (0.50 (0.26-0.97) p = 0.04) and no association with preschool wheeze.
Conclusion
Polymorphisms in ADAM33, ORMDL3/GSDMB and IL4 were associated with childhood asthma in a group of children with recurrent wheeze. The replication of the negative association of the CG/GG-genotype of rs528557 ADAM33 with childhood asthma in an independent birth cohort study confirms that a compromised ADAM33 gene may be implicated in the progression of wheeze into childhood asthma.

背景
哮喘候选基因在幼儿由喘息进展为哮喘的过程中所发挥的作用仍有待阐明。

目的
明确哮喘候选基因中的遗传变异与喘息进展为持续性喘息、最终发展为儿童哮喘之间的关联。

材料与方法
本前瞻性研究对来自ADEM（哮喘检测与监测，Asthma DEtection and Monitoring）队列的复发性喘息患儿进行随访，直至其年满6岁。在受试者6岁时，根据症状、肺功能及用药情况将其分为一过性喘息组或哮喘组。本研究针对198名儿童，采用logistic回归分析评估该分类结果与16个哮喘候选基因上的30个多态性位点之间的关联。若关联的P值小于0.10，则在独立出生队列KOALA研究（本分析纳入248名受试者）中进行验证分析。

结果
在ADEM队列中，ADAM33基因rs511898、rs528557位点以及ORMDL3/GSDMB基因rs7216389位点的次要等位基因与儿童哮喘的发生呈负相关；而IL4基因rs2243250、rs2070874位点的次要等位基因与儿童哮喘的发生呈正相关。在KOALA队列中进行验证分析时发现，ADAM33基因rs528557位点的CG/GG基因型与复发性喘息进展为儿童哮喘呈负相关（比值比0.50，95%置信区间0.26-0.97，P=0.04），而与学龄前喘息无关联。

结论
在复发性喘息患儿群体中，ADAM33、ORMDL3/GSDMB及IL4基因的多态性位点与儿童哮喘的发生存在关联。ADAM33基因rs528557位点CG/GG基因型与儿童哮喘的负相关关联在独立出生队列中得到验证，这证实功能受损的ADAM33基因可能参与喘息进展为儿童哮喘的过程。