Phenotypic and functional translation of IL33 genetics in asthma.

BACKGROUND: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

Integrated Allergy and Asthma Prevention and Care: Report of the MeDALL/AIRWAYS ICPs Meeting at the Ministry of Health and Care Services, Oslo, Norway.

Allergic diseases and asthma are increasing in prevalence globally. They can start early in life and many persist. It is important to prevent, detect and control these diseases early on and throughout life, so as to promote active and healthy ageing. The translational activities of MeDALL (Mechanisms of the Development of Allergy; EU FP7) are of great importance and include the deployment of successful allergy programmes. The Finnish Allergy Plan is a prototype for the prevention and control of severe allergic diseases. It has been considered for deployment to Norway by the Ministry of Health and Care Services in the frame of AIRWAYS ICPs (Integrated Care Pathways for Airway Diseases), a programme of Action Plan B3 of the EIP on AHA (European Innovation Partnership on Active and Healthy Ageing). Deployment of the Finnish and Norwegian Plans will make use of the scaling-up strategy of the EIP on AHA in regions in the European Union, and the WHO GARD (Global Alliance against Chronic Respiratory Diseases) globally. The regional deployment in Norway serves as a model of a national plan for the use of the EIP on AHA scaling-up strategy in other regions.