IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in childhood: The PASTURE/EFRAIM study

Background : IL-33 polymorphisms influences the susceptibility to asthma according to a GWAS. IL-33 can upregulate Regulatory T cells (Tregs) which are critical for healthy immune homeostasis. Aim : To investigate associations between IL-33 polymorphisms during development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. Methods : 829 children from the PASTURE/EFRAIM birth cohort were genotyped for IL-33 polymorphisms rs928413, rs1342326. In a subsample (n=99) of 4,5 years old children CD4+CD25highFOXP3+ Tregs were assessed by Flow cytometry following 24-hour-stimulation of peripheral blood mononuclear cells with PMA/Ionomycin or innate stimulus LPS or without stimuli. mRNA (ST2L, TLR4) expression and protein (sST2) levels ex vivo were measured in all 829 children by Real-Time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at age 6. Results: An increased risk for hay fever at the age of 6 years was observed for minor allele homozygotes of IL-33 polymorphisms rs928413 and rs1342326 (p=0.004; p=0.06). In parallel, CD4+CD25highFOXP3+ Tregs were decreased in minor allele homozygotes rs928413 (p=0.001) and rs1342326 (p=0.005) in unstimulated cells. mRNA Expression of ST2L, TLR4 and protein sST2 levels remained unchanged for both IL-33 polymorphisms. Conclusions: IL-33 rs928413 and rs1342326 polymorphisms were associated with increased risk for hay fever at the age of 6 years. Lower Tregs in minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.