IL1RL1 rs11685480 polymorphism is associated with IL-33/IL1RL1 pathway activity and asthma severity in a Japanese...

Severe asthma is characterized by frequent exacerbations and reduced quality of life. Determining the factors that influence disease severity is essential for optimizing treatment. Epithelial cell-derived cytokines, including interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), activate group 2 innate lymphoid cells, promoting type 2 inflammation. Genetic polymorphisms in the IL33 and TSLP genes, as well as their receptors interleukin-1 receptor-like 1 (IL1RL1) and interleukin-7 receptor (IL7R), have been linked to increased asthma susceptibility. The specific contributions of these polymorphisms to asthma pathogenesis remain undefined. This study examines the impact of genetic variations in epithelial cell-derived cytokine genes on asthma severity.

This observational study included 169 adults with asthma, of whom 53 had severe asthma. The analysis focused on ten polymorphisms with minor allele frequencies above 10 % in the IL33, IL1RL1, TSLP, and IL7R genes.

The A allele of the IL1RL1 rs11685480 polymorphism was a risk factor for severe asthma (odds ratio 3.54, 95 % confidence interval 1.17-10.72). This allele was associated with elevated IL1RL1 mRNA expression in T cells, which correlated with higher fractional exhaled nitric oxide (FeNO) levels and increased peripheral blood eosinophil counts. Additionally, this allele is linked to reduced plasma concentrations of soluble ST2 (sST2), and lower sST2 levels are associated with increased FeNO.

The IL1RL1 rs11685480 polymorphism is associated with severe asthma. This polymorphism increases IL1RL1 expression and decreases sST2 levels, intensifying type 2 inflammation. These results elucidate the mechanism by which this gene variant modulates the IL-33/IL1RL1 signaling axis.