rs3771175 — IL1RL1 IL1RL1 receptor variant

IL1RL1 rs3771175 — A Protective Variant in the ST2 Receptor Gene

The IL-33/ST2 signaling axis sits at the center of allergic disease biology. IL-33, an alarmin cytokine¹¹ alarmin cytokine
A danger signal released from damaged epithelial cells in the airways, skin, and gut that activates type 2 immunity via mast cells, eosinophils, and ILC2 innate lymphoid cells released during allergen exposure or viral infections, binds the ST2 receptor encoded by IL1RL1 on chromosome 2. IL1RL1 also generates a second splice form — soluble sST2 — that floats in the bloodstream and acts as a decoy, intercepting IL-33 before it can activate immune cells. Most well-studied IL1RL1 variants alter the balance between membrane-bound ST2 and soluble sST2. rs3771175 occupies a distinct position in this regulatory landscape: a 3'-UTR variant that increases total IL1RL1 expression and, in a large Chinese Han case-control study, is associated with reduced susceptibility to allergic rhinitis.

The Mechanism

rs3771175 sits in the 3'-untranslated region (3'UTR) of IL1RL1 at chromosome 2 position 102,343,750 (GRCh38), a region that controls transcript stability and translational efficiency rather than protein coding sequence. The minor A allele functions as a cis-eQTL²² cis-eQTL
an expression quantitative trait locus — a genetic variant that controls how much RNA is produced from the nearby gene, rather than altering the protein structure: carriers of the A allele show increased IL1RL1/ST2 expression in whole blood cells, a finding that reached statistical significance (p = 0.03) in a cross-sectional study of 506 individuals. rs3771175 is in complete linkage disequilibrium³³ linkage disequilibrium
LD r² = 1.0 means these two variants always travel together through the population — detecting one allele perfectly predicts the other with rs17639215, suggesting that the two SNPs tag the same functional haplotype.

How increased IL1RL1 expression translates to reduced allergic rhinitis risk is not fully resolved by the available evidence, but the most plausible interpretation draws on the IL1RL1 splicing architecture: the gene's two promoters differentially drive the soluble sST2 isoform (from the distal promoter) versus the membrane-bound ST2L isoform (from the proximal promoter). A 3'UTR variant increasing overall expression — particularly from the distal promoter's transcript — would expand the pool of circulating sST2 decoy receptor, increasing the capacity to intercept IL-33 before it reaches membrane-bound ST2L on mast cells and eosinophils. This would mirror the protective mechanism of the rs1420101 C allele, which is also associated with higher sST2 levels.

The Evidence

The primary allergy-relevant evidence comes from Li et al. (J Clin Lab Anal, 2022)⁴⁴ Li et al. (J Clin Lab Anal, 2022)
Association between IL1RL1 gene polymorphisms and allergic rhinitis risk in the Chinese Han population; 1,000 AR patients vs 1,000 controls, a well-powered case-control study of 1,000 allergic rhinitis patients and 1,000 healthy controls in the Chinese Han population. The rs3771175 A allele was associated with significantly reduced AR risk across multiple genetic models: OR 0.76 (p = 0.032) for heterozygous carriers, OR 0.76 (p = 0.031) under the dominant model, and OR 0.79 (p = 0.039) on a log-additive scale. Genotype frequencies in the study were TT 86.5% in cases versus 83.0% in controls, reflecting the protective shift with each A allele. A stratified sex analysis revealed a substantially stronger protective effect in males: heterozygous OR 0.45 (p = 0.001), dominant model OR 0.44 (p = 0.001), log-additive OR 0.48 (p = 0.001). This sex-stratified finding is notable given the sex differences in allergic rhinitis prevalence and suggests the variant's protective effect may operate through androgen- or sex-hormone-modulated IL-33/ST2 signaling. After false-discovery rate correction across the three IL1RL1 SNPs simultaneously, the association did not survive correction (FDR p = 0.075), which limits the strength of the current evidence to moderate — meaningful but not yet replicated in independent atopic cohorts.

The eQTL relationship was independently established in a Brazilian cohort (Trindade et al. PLoS One, 2023)⁵⁵ (Trindade et al. PLoS One, 2023)
Single nucleotide variants in IL33 and IL1RL1 (ST2) genes are associated with periodontitis and with Aggregatibacter actinomycetemcomitans; n=506: homozygous A/A carriers showed significantly elevated ST2 gene expression in whole blood cells. This confirms the regulatory nature of the variant and provides biological plausibility for the protective allergic rhinitis association, though the periodontal findings (elevated severe periodontitis risk in A carriers) highlight that increased ST2 expression can promote inflammation in tissues where IL-33 signalling is pathological rather than protective.

The broader context for this variant is the IL1RL1 locus's robust replication in atopic disease GWAS. Ferreira et al. (Nature Genetics, 2017)⁶⁶ Ferreira et al. (Nature Genetics, 2017) established the IL1RL1 locus among the top shared signals across asthma, hay fever, and eczema in 360,838 individuals, confirming that genetic regulation of the IL-33 receptor gene has consistent effects on the spectrum of atopic conditions.

Practical Implications

For individuals carrying the protective A allele, the reduced allergic rhinitis risk from this variant operates in the same IL-33/ST2 pathway as the more extensively studied rs1420101. In clinical terms, the A allele's protective effect is modest (OR ~0.76–0.79) and the evidence is currently single-population. Individuals who are TT homozygotes at rs3771175 — the most common genotype (~78% of the population) — do not carry the expression-boosting A allele and lack this specific protective modulation of IL1RL1 expression.

The ST2 eQTL connection points toward potential personalized monitoring: measuring serum sST2 levels (available as a clinical biomarker, routinely ordered in heart failure monitoring) provides a direct readout of the IL-33 decoy receptor output that this variant modulates. Lower sST2 in TT homozygotes with atopic symptoms supports more aggressive trigger avoidance and earlier consideration of type-2 pathway-targeting biologics.

Interactions

rs3771175 occupies the same IL-33/ST2 signaling axis as the primary IL1RL1 GWAS variants rs1420101 and rs11685480 (which regulate sST2 levels through promoter-specific eQTL effects) and the upstream IL33 variants rs1342326 and rs992969 (which regulate IL-33 ligand expression). As a 3'UTR variant with a distinct regulatory mechanism (transcript stability) from the intronic eQTLs at rs1420101, rs3771175 may additively modulate IL1RL1 expression alongside the promoter-acting variants. The receptor-side genetic architecture at this locus likely produces a range of sST2 outputs depending on which combination of these variants an individual carries. Direct compound studies combining rs3771175 with rs1420101 in atopic disease cohorts have not been published to date.