IL1RL1 asthma risk variants regulate airway type 2 inflammation

Area of Science:

• Immunogenetics
• Respiratory Medicine
• Molecular Biology

Background:

• Genome-wide association studies (GWAS) implicate the IL1RL1 gene in asthma susceptibility.
• The precise molecular mechanisms linking IL1RL1 variants to asthma pathogenesis remain unclear.
• IL1RL1 encodes the IL-33 receptor (ST2L) and a soluble decoy receptor (sST2), both involved in type 2 inflammation.

Purpose of the Study:

• To investigate the functional impact of IL1RL1 genetic variants on asthma risk.
• To elucidate the role of single nucleotide polymorphisms (SNPs) rs1420101 and rs11685480 in regulating ST2 levels and IL-33 signaling.

Main Methods:

• Association analysis of IL1RL1 SNPs (rs1420101, rs11685480) with plasma sST2 levels.
• Examination of expression quantitative trait loci (eQTL) for these SNPs in relevant lung tissues.
• Assessment of the additive effect of risk variants on type 2 airway inflammation in asthmatics.

Main Results:

• SNPs rs1420101 and rs11685480 are strongly associated with plasma sST2 levels.
• These SNPs function as eQTLs in airway epithelial cells and distal lung parenchyma, not whole blood.
• Genetically determined sST2 levels, originating from the lung, neutralize IL-33 activity.
• The identified SNPs additively increase the risk of airway type 2 inflammation in asthma patients.

Conclusions:

• Specific IL1RL1 SNPs (rs1420101, rs11685480) are associated with altered sST2 levels and function.
• These variants contribute to asthma risk by modulating IL-33 neutralization and promoting type 2 inflammation.
• A subset of asthmatics at risk of IL-33-driven type 2 inflammation can be defined by these genetic risk variants.