University of Groningen, University Medical Center Groningen, Department of Epidemiology, GRIAC Research Institute, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pediatrics, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.
Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Liege, Belgium.
J Allergy Clin Immunol. 2014 Jul;134(1):170-7. doi: 10.1016/j.jaci.2013.12.1080. Epub 2014 Feb 22.
Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway.
In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction.
Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated.
Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC.
IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.
全基因组关联研究确定了 IL33 和白细胞介素-1 受体样 1（IL1RL1）/白细胞介素 18 受体 1（IL18R1）是哮喘易感性基因座。IL33 和 IL1RL1 构成了一个单一的配体-受体途径。
在 2 个出生队列——儿童哮喘与变应原研究（PIAMA）和雅芳纵向研究父母和孩子（ALSPAC）中，我们分析了纵向喘息表型和哮喘与编码 IL-33、IL1RL1、其核心受体 IL1RAcP、其衔接子髓样分化初级反应基因 88（MyD88）和 Toll-IL-11 受体域包含衔接蛋白（TIRAP），以及下游的 IL-1 受体相关激酶 1、IL-1 受体相关激酶 4 和肿瘤坏死因子受体相关因子 6（TRAF6）的单核苷酸多态性（SNP）之间的关联。此外，我们还研究了该途径中的 SNP 是否存在可复制的基因-基因相互作用证据。
在 PIAMA 研究的 2007 名儿童和 ALSPAC 的 7247 名儿童中，共检测了 94 个 SNP。在每个队列中分析了与 8 岁时喘息表型和哮喘的关联，并进行了荟萃分析。通过 PIAMA 研究中的基于模型的多因子降维方法评估基因-基因相互作用，并进一步评估了 10 对 SNP 对的基因-基因相互作用。
在荟萃分析中，对多个测试进行校正后，IL33-IL1RL1 通路中的几个基因的 SNP 与中间发作性喘息相关：2 个 IL33 SNP（rs4742170 和 rs7037276）、1 个白细胞介素 1 受体辅助蛋白（IL1RAP）SNP（rs10513854）和 1 个 TRAF6 SNP（rs5030411）。晚发性喘息与 2 个 IL1RL1 SNP（rs10208293 和 rs13424006）相关，持续性喘息与 1 个 IL33 SNP（rs1342326）和 1 个 IL1RAP SNP（rs9290936）相关。IL33 和 IL1RL1 SNP 与哮喘呈名义相关。PIAMA 研究中有 3 个 SNP 对与哮喘存在交互作用，但在 ALSPAC 中没有。
IL33-IL1RL1 通路多态性与哮喘和特定的喘息表型有关；也就是说，大多数 SNP 与中间发作性喘息有关，这是一种与致敏密切相关的表型。我们推测，IL33-IL1RL1 通路多态性通过儿童早期的致敏作用影响喘息和随后哮喘的发展。
