Decoding asthma: Translating genetic variation in IL33 and IL1RL1 into disease pathophysiology

• Published in: Journal of allergy and clinical immunology Vol. 131; no. 3; pp. 856 - 865.e9
• Main Authors: Grotenboer, Néomi S., MSc, Ketelaar, Maria E., MSc, Koppelman, Gerard H., MD, PhD, Nawijn, Martijn C., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.03.2013; Elsevier
• Subjects: Allergy and Immunology; Animal models; Animals; Asthma - genetics; Asthma - immunology; Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; expression quantitative trait locus; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Predisposition to Disease; genome-wide association study; Humans; IL-1RL1; IL-33; Immunopathology; innate helper cells; innate type 2 lymphoid cells; Interleukin-33; Interleukins - genetics; Interleukins - immunology; Medical sciences; nuocytes; Pneumology; Polymorphism, Single Nucleotide; Receptors, Interleukin-1 Type I - genetics; Receptors, Interleukin-1 Type I - immunology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; ST2; MEX; IL-1 receptor–like 1; innate type 2 lymphoid cells; Linkage disequilibrium; RORA; MyD88; Utah residents with Northern and Western European ancestry from the CEPH collection (referred to as non-Hispanic white); GWA; ILC2; IL1RL1; NF-κB; YRI; Genome-wide association; SNP; innate helper cells; Toll-like/IL-1 receptor; TLR; Mexican ancestry in Los Angeles, California (referred to as Mexican population); Retinoic acid–related orphan receptor α; Toll-like receptor; African ancestry in Southwest United States; Nuclear factor κB; Myeloid differentiation primary response gene–88; ASW; Han Chinese in Beijing, China; IL-33; IL-18 receptor 1; ST2; expression quantitative trait locus; CEU; nuocytes; Yoruban in Ibadan, Nigeria; genome-wide association study; Type 2 innate lymphoid cell; IL-1RL1; LD; Single nucleotide polymorphism; CHB; TIR; IL18R1; Lymphoid cell; Genetic variability; Quantitative character; Helper cell; Association; Immunology; Translating; Bronchus disease; Obstructive pulmonary disease; Locus; Lung disease; Immunopathology; Pathophysiology; Respiratory disease; Cytokine; Genotype; Asthma; Genome; Polymorphism
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.11.028

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 TH 2 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 TH 2 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.