rs13408661 — IL1RL1

ST2 and the IL-33 Decoy Receptor: When Your Allergy Brake Has Less Grip

IL1RL1¹¹ IL1RL1
Interleukin-1 receptor-like 1, also known as ST2 — a member of the interleukin-1 receptor family that acts as the receptor for the cytokine IL-33 occupies a pivotal position in type 2 immunity: it controls how vigorously the immune system responds to allergens, parasites, and airway insults. The gene on chromosome 2q12.1 produces two functionally distinct proteins. The membrane-anchored form, ST2L, sits on the surface of mast cells, innate lymphoid cells, and type 2 helper T cells, transmitting the IL-33 alarm signal that drives eosinophilic inflammation, IgE production, and airway hyperreactivity. The soluble form, sST2, acts as a decoy receptor — it circulates in the blood, binds free IL-33 with high affinity, and prevents it from ever reaching the membrane receptor, effectively dampening the type 2 inflammatory response.

The rs13408661 variant is an intronic G>A substitution that tags a haplotype block influencing sST2 levels. Individuals carrying the A allele have lower circulating sST2, which means their IL-33 decoy system has reduced capacity — more IL-33 remains free to activate mast cells, ILC2s, and eosinophils.

The Mechanism

IL1RL1 alternative splicing governs the ST2L/sST2 ratio. The full-length ST2L isoform contains all extracellular immunoglobulin-like domains plus a transmembrane helix and intracellular TIR signaling domain²² TIR signaling domain
Toll/interleukin-1 receptor domain — the conserved cytoplasmic region that recruits adaptor proteins (MyD88, IRAK4) to propagate the inflammatory signal. The sST2 isoform uses an alternative proximal promoter and lacks the transmembrane and TIR domains, so it is secreted rather than anchored to the cell surface.

Gordon et al. (2016)³³ Gordon et al. (2016)
JCI Insight 2016;1(14):e87871; UCSF and National Jewish Health; n=127–237 airway epithelial and lung parenchyma samples showed that GWAS risk alleles within the IL1RL1 locus operate through tissue-specific promoter elements: rs1420101 (a proxy for the rs13408661 haplotype) downregulates sST2 expression in airway epithelial cells via the proximal promoter, while rs11685480 operates in lung parenchyma via the distal promoter. In both tissues, the risk haplotype reduces the decoy receptor supply. Without adequate sST2 to sequester circulating IL-33, more IL-33 reaches ST2L on mast cells and ILC2s, sustaining type 2 cytokine production (IL-4, IL-5, IL-13) and eosinophil recruitment.

The Evidence

The association between this locus and asthma was first reported at genome-wide significance by the APCAT consortium⁴⁴ APCAT consortium
Ramasamy et al., PLoS One 2012;7(9):e44008; six European-descent population-based cohorts, 1,716 asthma cases and 16,888 controls. The consortium identified rs13408661 near IL1RL1/IL18R1 with P=1.1×10⁻⁹, correlated with the previously reported rs3771180, confirming the locus in an independent European dataset. The IL1RL1 locus association was subsequently replicated across European, African, and Latino ancestries in the CAAPA meta-analysis⁵⁵ CAAPA meta-analysis
Torgerson et al., Nature Genetics 2011;43:887–892; 5,416 asthma cases, replication in 12,649 individuals, establishing it as one of the most robustly replicated asthma susceptibility loci.

The functional link between the rs13408661 A-allele haplotype and sST2 biology is confirmed by the Teräsjärvi 2024 birth cohort study, which found that rs13408661 variant carriers had substantially lower serum sST2 concentrations⁶⁶ substantially lower serum sST2 concentrations
p<0.0001; AC/AA genotype group median sST2 ~2,453 pg/mL versus CC carriers ~5,437 pg/mL at the linked rs1041973 locus, and children with these variants showed a trend toward higher asthma incidence, though the sample (146 Finnish children) was underpowered to reach statistical significance on its own. The Riikonen et al. 2022 study⁷⁷ Riikonen et al. 2022 study
Acta Paediatrica 2022;111(3):628–635; n=125–141 children followed to age 5–7 and 11–13 years after infant bronchiolitis hospitalization found the rs13408661 variant genotype consistently associated with persistent post-bronchiolitis asthma across multiple definitions at both follow-up time points, though the association attenuated when maternal asthma and early atopic dermatitis were controlled for — suggesting that the genetic effect may operate partly through shared familial pathways.

The functional translation of the locus is further supported by the Gordon et al. finding that carriers of 3–4 IL1RL1 risk alleles (spanning the rs13408661 haplotype region) had 2.85-fold increased odds of type 2 airway inflammation⁸⁸ 2.85-fold increased odds of type 2 airway inflammation — the eosinophilic, high-FeNO, steroid-responsive endotype that is clinically tractable. The locus effect appears particularly relevant for this type 2-high phenotype rather than neutrophilic or mixed asthma.

Practical Actions

Individuals carrying the A allele — particularly GA heterozygotes who represent roughly 29% of the global population and AA homozygotes (~3%) — have a sST2 system that is somewhat less effective at buffering IL-33 surges. In practical terms, this means the type 2 inflammatory signaling cascade (mast cell degranulation, IgE production, eosinophil recruitment) may be easier to trigger and harder to switch off after allergen or respiratory virus exposure.

The most directly actionable implication is to minimize IL-33-triggering exposures: allergen load reduction, viral respiratory illness prevention (which is a potent IL-33 trigger in the airway epithelium), and monitoring lung function during respiratory infections. For individuals with diagnosed asthma or allergic rhinitis who carry the A allele, the type 2-high phenotype (elevated blood or sputum eosinophils, elevated FeNO) is more likely, which has implications for which controller therapies are likely to be effective.

Interactions

rs13408661 sits on chromosome 2q12.1 within a broader IL1RL1/IL18R1/IL18RAP gene cluster. The locus contains at least four independent association signals for asthma and related traits (as characterized by Portelli et al. 2020, PMID 32324168), of which rs13408661 tags a haplotype overlapping with the major Signal A (rs995514 proxy for rs12474258). Other SNPs in the same haplotype block — particularly rs1420101, rs11685480, rs1041973, and rs1921622 — regulate sST2 expression through different promoters and in different tissues, and their effects are partially independent.

The biologically paired variant on chromosome 9p24.1 is IL-33 itself (rs146597587 in IL33), the ligand for ST2. Individuals who carry both an IL1RL1 A-allele (reduced sST2 decoy) and an IL33 high-expression variant would be expected to have compounded type 2 inflammatory drive — more IL-33 produced and less decoy to neutralize it — though this specific combination has not been directly studied in a single cohort.