rs950881 — IL1RL1 IL1RL1 intronic variant

IL1RL1 rs950881 — A Second IL-33 Receptor Variant Linked to Allergic Rhinitis Protection

The IL1RL1 gene encodes ST2¹¹ ST2
ST2 (Suppression of Tumorigenicity 2) is the surface receptor for the alarmin cytokine IL-33. When activated by IL-33 released from damaged airway epithelium or skin, ST2 triggers type 2 immune responses that drive allergic inflammation, the primary receptor for the alarmin cytokine IL-33. Positioned on chromosome 2q12 — the most replicated genetic locus for atopic disease in the human genome — IL1RL1 sits in a dense cluster of interleukin-1 receptor family genes that collectively calibrate how strongly the immune system responds to inhaled and ingested allergens. The rs950881 variant lies within an intron of IL1RL1 at position 102,316,052 on GRCh38 (NC_000002.12), approximately 4 kb downstream of the companion intronic variant rs72823628 in the same gene.

The Mechanism

IL1RL1 produces at least two functionally distinct isoforms through alternative splicing: membrane-bound ST2L²² ST2L
ST2L is the full-length, cell-surface form; it forms a signaling complex with IL-1RAcP, activates MyD88, and drives NF-κB and MAPK cascades that produce IL-4, IL-5, and IL-13 — the cytokines that define type 2 allergic inflammation, which drives allergic inflammation, and soluble sST2³³ sST2
sST2 is a truncated secreted form lacking the transmembrane and intracellular domains; it binds IL-33 in circulation without transducing a signal, acting as a decoy that quenches IL-33 before it can activate ST2L, which acts as a circulating decoy receptor that binds and neutralizes IL-33 before it can activate membrane-bound ST2. Higher circulating sST2 levels correlate with lower blood eosinophil counts and a dampened allergic phenotype. Intronic variants in IL1RL1, including rs950881, likely influence this sST2/ST2L ratio or overall receptor expression levels in airway-relevant immune cells, reducing the amplitude of IL-33-triggered type 2 inflammation in T-allele carriers.

The Evidence

The IL1RL1/IL18R1 locus on 2q12 is among the most robustly replicated allergy susceptibility signals in the genome. Moffatt et al. 2010⁴⁴ Moffatt et al. 2010
A large-scale, consortium-based genomewide association study of asthma. NEJM 363:1211–1221, n=26,475 (10,365 cases + 16,110 controls) established the locus at genome-wide significance for asthma (p=3×10⁻⁹), and Ferreira et al. 2017⁵⁵ Ferreira et al. 2017
Nature Genetics, n=360,838; 136 independent risk variants for asthma, hay fever, and eczema combined; IL1RL1/IL18R1 among the most replicated across all three conditions extended this association across all three major atopic phenotypes — asthma, allergic rhinitis, and eczema — confirming shared genetic architecture.

For rs950881 specifically, a case-control study in the Chinese Han population⁶⁶ case-control study in the Chinese Han population
Li et al. J Clin Lab Anal 2022, 36(11):e24747; 1,000 AR patients and 1,000 controls; genotyping by Agena MassARRAY; false discovery rate and false positive report probability corrections applied found that the T allele was associated with significantly reduced allergic rhinitis risk, mirroring the protective patterns seen for companion variants rs72823628 and rs3771175 in the same study. The effect was most pronounced in male participants. Savenije et al. 2014⁷⁷ Savenije et al. 2014
PIAMA cohort, n=2,007; ALSPAC cohort, n=7,247; 94 SNPs across 8 IL33-IL1RL1 pathway genes further showed that IL1RL1 pathway variants particularly influence late-onset wheeze — the phenotype most closely linked to persistent allergic sensitization.

Molecularly, the IL1RL1 locus contains strong cis-eQTL signals for sST2 protein levels: Dijk et al. 2018⁸⁸ Dijk et al. 2018
Eur Respir J, n=multi-cohort; rs1420101 most significant eQTL for IL1RL1-a (sST2) at p=2.8×10⁻⁵⁶; sST2 levels negatively correlate with blood eosinophil counts demonstrated that intronic variation at this locus strongly predicts circulating sST2 levels, which in turn inversely track with eosinophil-driven allergic inflammation. rs950881 likely participates in the same regulatory architecture given its co-localization and co-association with rs72823628.

The T allele is rare in most populations: approximately 7.7% in Europeans, 11.8% in Africans, 2% in East Asians, and less than 1% in South Asians. This means the GG genotype (standard susceptibility configuration) is the reference state for the vast majority of people globally.

Practical Actions

The GG genotype at rs950881 does not indicate disease — most people carry this genotype and do not develop allergic rhinitis. However, GG carriers lack the additional IL-33 signaling dampening conferred by the T allele, placing the allergic response threshold at the population-average level for this locus. For individuals who develop seasonal or perennial nasal symptoms, earlier IgE-based evaluation and targeted allergen avoidance can reduce progression to chronic sensitization or asthma.

GT and TT carriers have at least one copy of the protective T allele, associated with reduced IL-33/ST2 signaling amplitude and a lower risk of allergic rhinitis in this population. This does not confer immunity to allergic disease — many other genetic and environmental factors determine whether allergy manifests — but it shifts the sensitization threshold, a meaningful effect in high-allergen environments.

Interactions

rs950881 sits approximately 4 kb from rs72823628 in the same IL1RL1 intron and was co-studied in the Li et al. 2022 report, with both showing protective T and A alleles respectively. Their independent contribution versus LD-tagging of the same signal has not been fully dissected; together they may represent a haplotype block capturing a single regulatory element, or they may tag independent functional changes. The upstream IL-33 ligand locus (rs1342326 near IL33) represents the other end of the signaling axis: individuals carrying both higher IL-33 production alleles and the standard GG genotype at rs950881 would have amplified input signal and uninhibited receptor response — a potential compound effect worth considering in families with strong atopic history. Interaction between IL33 and IL1RL1 pathway variants has been examined in the Savenije 2014 cohort study, which identified SNP-pair effects for childhood asthma phenotypes.