Genetic Signals In IL33 Associate With An Eosinophilic Subphenotype Of Asthma And With IL33 Expression In Bronchial Epithelium

Cellular and molecular mechanisms (English)

Maria E. Ketelaar
University of Groningen, University Medical Center Groningen (UMCG), Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands, Pediatric Pulmonology&Allergology, Pathology&Medical Biology
BEKIJK PROGRAMMA
 
09 april 14:54 - 15:12 (Markgraaf 2)
Background:
Asthma is a heterogeneous pulmonary disease, influenced by both environmental and genetic factors. Single nucleotide polymorphisms (SNPs) in the genes encoding the cytokine IL-33 (IL33) and its receptor IL-1RL1 (IL1RL1) have repeatedly and consistently been associated with asthma in genomewide and candidate gene based genetic studies. In asthma patients, levels of IL-33 have been found elevated in induced sputum, the airway epithelium and bronchial lavage fluid.
Rationale:
Although these studies suggest dysregulation of the IL33 pathway in asthma, few have investigated whether IL33 associates with specific subtypes of asthma. Similarly, the functional relevance of asthma associated SNPs spanning IL33 is not fully understood.
Hypothesis:
In the current study, we hypothesized that SNPs in IL33 associate with specific subfeatures of asthma and that these SNPs could influence the activity of the IL33 pathway via altered gene expression in bronchial epithelium. We also hypothesized that sustained IL33 expression could attenuate bronchial epithelial cell function.
Methods&Results:
By regression modelling we associated SNPs at the IL33 locus with blood eosinophils, blood neutrophils and lung function (FEV1, FEV1/FVC) in the Dutch asthma GWAS (DAG) cohort and in a large Dutch general population cohort (LIFELINES). A genetic signal spanning 75kb 5’of IL33 and the first intron of IL33 was associated with eosinophilic asthma (tagged by rs992969, OR=1.33, SE=0.10, p=7.84E-05 comparing n=543 asthmatics having blood eosinophil levels >150cells/uL vs. n=6863 healthy controls). The same signal positively associated with level of blood eosinophils in the general population (beta=0.05, SE=0.01, p= 9.04E-07, n=13,395). Interestingly, this genetic signal was associated with IL33 mRNA expression levels in bronchial epithelial samples (beta=0.33+/-SD0.043, p=8.30E-12, n=139 healthy subjects). Lentiviral overexpression of IL33 in primary human bronchial epithelial cells (n=5) resulted in reduced vitality and viability, but had no effect on barrier function in our model.
In conclusion:
The current study shows that genetic signals in the IL33 region associate with an eosinophilic subtype of asthma and with (higher) IL33 expression, yet functional effects of overexpression of IL33 on the epithelium is limited.

IL33 genetic polymorphisms associate with eosinophilic asthma (P<10E-5)

The eosinophilic asthma-signal associates with IL33 mRNA expression in bronchial epithelium (P<10E-11)

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