RESUMEN
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.
Asunto(s)
Asma , Regulación de la Expresión Génica/inmunología , Predisposición Genética a la Enfermedad , Interleucina-33 , Polimorfismo de Nucleótido Simple , Adulto , Asma/genética , Asma/inmunología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Interleucina-33/genética , Interleucina-33/inmunología , Masculino , Persona de Mediana EdadRESUMEN
The extensive pulmonary vasculature results in the lungs being intimately exposed to circulating blood. As increased serum osmolality may be associated with an increase in pro-inflammatory activity, this has the potential to result in damage to the lungs and reduced lung function. The objective of the present study was to test the hypothesis that increased serum osmolality is associated with a lower forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). The present study was a cross-sectional study of 10,602 participants in the Third National Health and Nutrition Examination Survey aged > or = 17 yrs for whom there were adequate data on all outcomes and exposures. After adjustment for age, smoking and other confounding factors, increased serum osmolality was inversely associated with both FEV(1) and FVC. An increase of 1 sd in serum osmolality was associated with a decrease in both FEV(1) of 19.8 mL and FVC of 35.3 mL. The constituent assays demonstrated a complex relationship with both FEV(1) and FVC. Increased serum osmolality was associated with decreased forced expiratory volume in one second and forced vital capacity. If causal, this may have implications for the understanding of the processes that are involved in the pathophysiology of decline in lung function.
