rs3771166 — IL1RL1/IL18R1

IL18R1 and the IL-33/IL-18 Receptor Cluster — The GABRIEL Asthma Locus

When the GABRIEL Consortium published the largest asthma genome-wide association study of its era in 2010, one of the five genome-wide significant signals landed squarely on chromosome 2q12 — a dense cluster of interleukin-1 receptor family genes including IL1RL1 (ST2)¹¹ IL1RL1 (ST2)
The receptor for IL-33; encodes the ST2 protein that triggers type 2 immune responses when bound by the alarmin cytokine IL-33 and IL18R1²² IL18R1
Encodes the IL-18 receptor subunit 1, which partners with IL18RAP to form the functional IL-18 receptor complex. rs3771166 is the lead tag SNP for this locus, sitting within an intron of IL18R1 approximately 17 kb downstream of IL1RL1.

The Mechanism

rs3771166 is an intronic variant in IL18R1 that acts as a tag for regulatory variation across the entire IL1RL1/IL18R1/IL18RAP gene cluster. The 2q12.1 locus is a tightly packed receptor family cluster in which multiple variants are in partial linkage disequilibrium with one another. The G risk allele at rs3771166 captures the cumulative regulatory signal affecting expression of both IL18R1 (the IL-18 receptor) and nearby IL1RL1 (the IL-33 receptor / ST2). IL-18 and IL-33 are distinct but complementary alarmins³³ alarmins
Damage-associated cytokines released by stressed or dying epithelial cells; they activate innate immune sentinels without requiring pathogen-specific recognition that coordinate early type 2 immune activation. IL-18 can promote both Th1 responses (with IL-12) and amplify Th2/ILC2 responses (without IL-12), making IL18R1 expression a context-dependent modulator of airway inflammation magnitude.

The Evidence

Moffatt et al. (NEJM, 2010)⁴⁴ Moffatt et al. (NEJM, 2010)
A large-scale, consortium-based genomewide association study of asthma. NEJM 363:1211–1221 established rs3771166 as the lead signal at 2q12 with p=3×10⁻⁹ in 10,365 asthma cases and 16,110 controls, making it one of only five loci to reach genome-wide significance in what was then the largest asthma GWAS. The G allele confers an odds ratio of approximately 1.15 per copy (95% CI 1.10–1.20), placing it in the moderate-effect range typical of complex disease susceptibility variants.

The finding replicated across ancestry groups. Torgerson et al. (Nature Genetics, 2011)⁵⁵ Torgerson et al. (Nature Genetics, 2011)
Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations confirmed the IL1RL1 locus in European American, African American, and Latino cohorts, demonstrating that this signal is not population-specific. Wan et al. (Thorax, 2012)⁶⁶ Wan et al. (Thorax, 2012)
Genome-wide association study to identify genetic determinants of severe asthma extended the finding to severe asthma specifically, with the 2q12 locus achieving p=5.59×10⁻⁸.

Savenije et al. (JACI, 2014)⁷⁷ Savenije et al. (JACI, 2014)
Association of IL33-IL1RL1 pathway polymorphisms with wheezing phenotypes in childhood showed that different variants within this locus associate with distinct wheezing trajectories in birth cohorts — late-onset wheeze maps specifically to IL1RL1 variants, highlighting how functional heterogeneity within the cluster shapes disease phenotype.

Practical Actions

The G allele at rs3771166 modestly elevates asthma and atopic airway disease risk, operating through the shared IL-18R/ST2 signaling axis. While rs3771166 itself is a tag SNP (its effect is attributed to regulatory changes across the locus rather than a direct protein change), the downstream consequences are identical to other variants in the cluster: reduced threshold for IL-33- and IL-18-driven type 2 airway inflammation.

G risk allele carriers benefit from early-warning monitoring of eosinophil counts, which reflect active type 2 inflammation through this pathway. For AG heterozygotes, standard monitoring suffices. For GG homozygotes — who carry the full additive genetic load at this locus — proactive lung function surveillance and early escalation of asthma treatment are well-supported by the evidence.

Interactions

rs3771166 is part of the same chromosomal locus as rs1420101 (the primary IL1RL1 eQTL for sST2 decoy receptor levels). These SNPs tag partially overlapping but potentially independent signals within the 2q12.1 cluster. Carrying risk alleles at both rs3771166 and rs1420101 may confer additive susceptibility, as each tags different functional elements within the IL1RL1/IL18R1/IL18RAP regulatory architecture.

The upstream IL33 gene variants rs992969 and rs1342326 are pathway partners: they increase IL-33 ligand production, which must then be buffered by the ST2/sST2 system partly regulated by this locus. Individuals with risk alleles across multiple nodes of the IL-33/ST2 axis (ligand, receptor, decoy) accumulate additive susceptibility.