IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma
IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma
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DOI：
10.1016/j.jaci.2005.10.024
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发表时间：
2006-02-01
影响因子：
14.2
通讯作者：
von Mutius, E
中科院分区：
文献类型：
--
作者：
Kabesch, M;Schedel, M;von Mutius, E
背景：作为哮喘和特应性疾病的标志，IgE的产生可能受遗传控制。IL-4和IL-13通路的基因是IgE调控的核心，迄今为止只在单基因作用的研究中进行了评估。目的：本文分析了包括IL-4、IL-13及其共享受体链IL-4R α和细胞内信号转导和转录激活因子STAT6在内的组合扩展单倍型，以评估单核苷酸多态性在这一重要免疫信号通路中的联合作用。方法：我们对1120名9至11岁的儿童进行了基因分型，在IL-4/IL-13通路的各自基因中发现了18个多态性。每个基因选择一个多态性，因为其假定的功能作用，并通过使用Cordell模型评估基因间相互作用，逐步建立扩展单倍型。结果：与单基因多态性的最大影响相比，将所有4个主要途径基因的多态性逐步结合，血清IgE水平升高的风险增加10.8倍（P = 0.02），哮喘发生的风险增加16.8倍（P = 0.005）。在具有加性和显性效应的模型中，对哮喘的一对和三胞胎组合（最低P = 0.005）以及对IgE调节的多态性（最低P = 0.054）均观察到显著的相互作用。结论：这些数据表明，只有联合分析IL-4/IL-13通路的遗传改变才能揭示其在特应性和儿童哮喘发生中的实际意义。
Background: IgE production, a hallmark of asthma and atopic disease, may be under genetic control. Genes of the IL-4 and IL-13 pathway, central for IgE regulation, have so far only been assessed in studies of single gene effects.Objective: Here we analyzed combined extended haplotypes involving IL-4, IL-13, their shared receptor chain IL-4R alpha, and the intracellular signal transducer and activator of transcription, STAT6, to assess the combined effect of single nucleotide polymorphisms in this important immunological signaling pathway.Methods: We genotyped a large cross-sectional population of 1120 children age 9 to 11 years for 18 polymorphisms in the respective genes of the IL-4/IL-13 pathway. One polymorphism per gene was selected because of its putative functional role, and extended haplotypes were built in a stepwise procedure where gene-by-gene interactions were assessed by using a Cordell model.Results: Combining polymorphisms in all 4 major pathway genes in a stepwise procedure, the risk for high serum IgE levels increased 10.8-fold (P = .02) and the risk for the development of asthma increased by a factor of 16.8-fold (P = .005) compared with the maximum effect of any single polymorphism. Significant interactions in a model with additive and dominant effects, for both pair and triplet combinations for asthma (lowest P = .005), and for pairs of polymorphisms in IgE regulation were observed (lowest P = .054).Conclusion: These data indicate that only the combined analyses of genetic alterations in the IL-4/IL-13 pathway reveal its actual significance to the development of atopy and childhood asthma.