rs1420101 — IL1RL1

IL1RL1 and the IL-33 Alarm System — When Your Genetic Decoy Is Turned Down

Your immune system uses a signaling molecule called IL-33¹¹ IL-33
Interleukin-33, a cytokine released by damaged epithelial cells lining the airways, skin, and gut — it acts as an early-warning alarm for allergens, parasites, and tissue injury to raise the alarm when the body's barrier tissues are threatened. IL1RL1 encodes the ST2 receptor that detects this alarm. But the gene also produces a second, soluble form of the receptor — sST2 — that floats freely in the bloodstream and acts as a decoy, intercepting IL-33 before it can activate immune cells. The balance between membrane-bound ST2 (which passes the alarm signal through) and soluble sST2 (which silences it) is a critical tuning dial for type 2 immune responses. rs1420101 sits at that dial.

The Mechanism

rs1420101 is an intronic eQTL²² eQTL
expression quantitative trait locus — a genetic variant that controls how much of a gene's product is made, rather than changing the protein structure itself in airway epithelial cells. The T risk allele shifts the expression balance away from the soluble sST2 decoy and toward the membrane-bound signaling form. With less circulating sST2 to intercept it, IL-33 reaches immune cells more readily, driving type 2 inflammation³³ type 2 inflammation
A class of immune response dominated by eosinophils, mast cells, and IgE, characteristic of asthma, hay fever, eczema, and nasal polyps. The effect is dose-dependent: each copy of the T allele progressively lowers sST2. The C allele has the opposite effect — it is the strongest known pQTL for circulating sST2 protein, with the association reaching p=2.8×10⁻⁵⁶ in over 1,400 participants.

The Evidence

The IL1RL1 locus is one of the most replicated genetic signals in atopic disease. Ferreira et al. (Nature Genetics, 2017)⁴⁴ Ferreira et al. (Nature Genetics, 2017)
Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nature Genetics 49:1752–1757 identified the locus among the top shared risk signals in a meta-analysis of 360,838 individuals, confirming that the same variant influences asthma, hay fever, and eczema together — not as separate diseases but as expressions of a shared underlying biology.

Demenais et al. (Nature Genetics, 2018)⁵⁵ Demenais et al. (Nature Genetics, 2018)
Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nature Genetics 50:42–53 quantified the T allele effect at OR 1.12 (p=4×10⁻²¹) for asthma in a multi-ethnic dataset.

Gordon et al. (JCI Insight, 2016)⁶⁶ Gordon et al. (JCI Insight, 2016)
IL1RL1 asthma risk variants regulate airway type 2 inflammation provided the mechanistic link: in airway epithelial cells from 127–141 individuals, T allele carriers showed lower sST2 expression under both baseline and IL-13-stimulated conditions. Carriers of 3–4 risk alleles across rs1420101 and the nearby rs11685480 had an OR of 2.85 for the type-2-high asthma endotype.

Dijk et al. (Eur Respir J, 2018)⁷⁷ Dijk et al. (Eur Respir J, 2018)
Genetic regulation of IL1RL1 methylation and IL1RL1-a protein levels in asthma confirmed the pQTL signal in 1,462 participants — rs1420101 is the dominant genetic driver of circulating sST2 levels, explaining a substantial fraction of inter-individual variability.

Clinically, the TT genotype has been linked to better outcomes with targeted biologic therapy: Nishi et al. (ERJ Open Res, 2025)⁸⁸ Nishi et al. (ERJ Open Res, 2025)
IL1RL1 variant may affect the response to type 2 biologics in patients with severe asthma found that TT carriers achieved excellent Global Evaluation of Treatment Effectiveness (GETE) scores on benralizumab and other anti-IL-5 therapies, making the variant a candidate pharmacogenomic predictor. The biological logic is direct: TT genotype → low sST2 → high IL-33 signaling → eosinophil-driven inflammation → high sensitivity to eosinophil-depleting anti-IL-5 blockade.

Practical Actions

For CC homozygotes, the high circulating sST2 acts as an effective IL-33 buffer — standard allergen avoidance and treatment approaches are sufficient. For CT and TT carriers, the reduced decoy receptor buffer means the threshold for IL-33-driven inflammation is lower, which translates to practical differences in monitoring and trigger management.

TT carriers with severe asthma who have not responded well to inhaled corticosteroids or leukotriene antagonists may benefit from earlier consideration of anti-IL-5 biologics, given the evidence of TT-genotype-specific response. sST2 serum measurement is available as a clinical biomarker — it is routinely measured in heart failure monitoring and can reflect IL-33 pathway activity across conditions.

Interactions

The strongest documented interaction is with the nearby IL1RL1 variant rs11685480. Gordon et al. (2016) showed that combining T alleles at rs1420101 with risk alleles at rs11685480 yields an OR of 2.85 for type-2-high asthma — substantially greater than either variant alone. The two SNPs tag partially overlapping but independent signals within the gene's regulatory architecture. A compound action capturing the combined risk of carrying T alleles at both loci would be informative for severe asthma risk stratification and biologic therapy selection.

IL-33 pathway variants in the upstream IL33 gene (including rs992969 and rs1929992) can further amplify risk by increasing the amount of IL-33 ligand that must be buffered by sST2.