RESUMO
The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
Assuntos
Asma/genética , Predisposição Genética para Doença/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Asma/imunologia , Genótipo , Humanos , Pulmão/imunologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Mucosa Respiratória/imunologiaRESUMO
Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101).IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.
Assuntos
Asma/genética , Metilação de DNA , Regulação da Expressão Gênica , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Asthma is a complex disease that results from the interaction between genetic predisposition and environmental factors. Recently, genome-wide association studies have identified a number of genes that significantly contribute to asthma. Two of these genes, IL33 and IL-1 receptor-like 1 (IL1RL1), act in one signal transduction pathway. IL33 encodes a cytokine released on damage of cells, whereas IL1RL1 encodes part of the IL-33 receptor complex. Recent progress made in functional studies in human subjects and mouse models of allergic airway disease indicate a central role of IL-33 signaling in driving TH2 inflammation, which is central to eosinophilic allergic asthma. Here, IL-33 acts on cells of both the adaptive and innate immune systems. Very recently, a novel population of IL-33-responsive innate immune cells, the type 2 innate lymphoid cells, was found to produce hallmark TH2 cytokines, such as IL-5 and IL-13. The relevance of these cells for asthma is underscored by the identification of retinoic acid-related orphan receptor α(RORA), the gene encoding the transcription factor critical for their differentiation, as another asthma gene in genome-wide association studies. This review describes the mechanisms through which genetic variation at the IL33 and IL1RL1 loci translates into increased susceptibility for asthma. We propose that genetic variation associated with asthma at the IL33 and IL1RL1 loci can be dissected into independent signals with distinct functional consequences for this pathway that is central to asthma pathogenesis.
