rs10208293 — IL1RL1

IL1RL1 (ST2) — A Second Independent Switch in the IL-33 Alarm System

The IL1RL1 gene¹¹ IL1RL1 gene
Interleukin-1 Receptor-Like 1, encoding the ST2 protein — the cell-surface receptor through which IL-33 activates mast cells, eosinophils, ILC2s, and Th2 lymphocytes is home to one of the most replicated loci in allergy genetics. Most people who have heard of ST2 genetics know about rs1420101 — the primary GWAS signal, located roughly 8.6 kilobases away on the same gene. But rs10208293 is something different: a second, statistically independent signal at the same locus that tracks a distinct biological mechanism and a specific clinical phenotype not captured by rs1420101 alone.

The IL-33/ST2 axis works like an epithelial alarm system. When airway or skin cells are damaged — by viruses, allergens, or pollutants — they release IL-33²² IL-33
A nuclear alarmin cytokine that, when released from damaged cells, binds to ST2 on innate lymphoid cells type 2 (ILC2s), mast cells, and eosinophils, triggering a rapid Th2 inflammatory cascade. The ST2 receptor exists in two forms: a membrane-bound signalling receptor that amplifies inflammation, and a soluble decoy receptor (sST2) that mops up free IL-33 and dampens the alarm. The ratio of membrane-bound to soluble ST2 determines how strongly any given tissue responds to an IL-33 signal. Both rs1420101 and rs10208293 influence this ratio — but at different regulatory elements and to different effect.

The Mechanism

rs10208293 sits at position 102,349,850 on chromosome 2 (GRCh38), within an intron of IL1RL1. Like most regulatory intronic variants, it is presumed to act through an expression quantitative trait locus (eQTL) mechanism — altering how the gene is spliced or expressed in specific cell types rather than changing the protein sequence. The A allele tags a haplotype that modulates the balance between transmembrane IL1RL1 isoforms and the soluble decoy sST2.

The key observation is that rs10208293 is statistically independent from rs1420101 — the two variants carry separate signals in conditional analyses, meaning both must be genotyped to fully characterise a person's IL1RL1 haplotype. Their effects on sST2 levels are not additive duplicates of each other; they reflect distinct molecular mechanisms at the same gene, likely involving different regulatory elements or alternative splicing events across different tissues.

The Evidence

The variant's clinical significance was established in two convergent lines of evidence. The landmark Ferreira et al. GWAS in Nature Genetics³³ Ferreira et al. GWAS in Nature Genetics analysed 360,838 participants and identified 136 independent risk variants for allergic disease (asthma, hay fever, and eczema considered jointly); rs10208293 emerged as an independent IL1RL1 signal in conditional analyses, confirming it is not simply a proxy for rs1420101.

The phenotypic specificity was worked out in a two-cohort meta-analysis by Savenije et al. (2014)⁴⁴ Savenije et al. (2014), which followed children in the PIAMA (n=2,007) and ALSPAC (n=7,247) birth cohorts. Crucially, this study distinguished wheezing phenotypes: early-transient, early-persistent, and late-onset wheeze. rs10208293 was one of exactly two IL1RL1 SNPs that associated specifically with late-onset wheeze — the phenotype that is most strongly predictive of persistent asthma in adulthood. This phenotypic specificity is clinically meaningful: children who develop wheeze only after age 4-6 years, rather than during toddlerhood, carry a different underlying immunological trajectory that rs10208293 appears to tag.

The biological link to airway inflammation is corroborated by the FeNO connection. Ketelaar et al. (2017)⁵⁵ Ketelaar et al. (2017) showed that circulating sST2 levels in preschool wheezers predict which children develop the eosinophilic subtype of asthma — defined by elevated FeNO⁶⁶ FeNO
Fractional exhaled nitric oxide, a non-invasive breath test that measures eosinophilic airway inflammation; levels above 25 ppb in adults and 20 ppb in children indicate eosinophilic inflammation (ATS/ERS guidelines) (AUC=0.65). Since rs10208293 is a regulatory variant affecting sST2 balance, carriers of the A allele have altered sST2 circulating levels that influence this eosinophilic trajectory.

Evidence from the Iranian population study⁷⁷ Iranian population study (126 asthmatics, 300 controls) further confirmed the AA genotype's association with asthma susceptibility (p=0.028). Population-specific data from Chinese Han children (Wu et al. 2021, PMID 34977013) showed an apparently different direction — the A allele appearing protective in that cohort — consistent with different linkage disequilibrium structure around the locus at low A allele frequency (~13%) in East Asian populations. This does not contradict the European GWAS data; it reflects a well-documented phenomenon where tagging SNPs for a causal variant show opposite directions when allele frequencies differ markedly across ancestries.

Practical Implications

For A allele carriers, the actionable insight centres on eosinophilic airway monitoring rather than general asthma management. The IL1RL1 locus specifically predicts the eosinophilic, Th2-driven subtype of airway disease — the subtype that responds to FeNO-guided treatment decisions and to biologics targeting the IL-33/ST2 pathway (itepekimab) or eosinophil biology (dupilumab, benralizumab, mepolizumab). Knowing that rs10208293 tags this phenotype specifically makes FeNO testing the highest-yield monitoring approach for A allele carriers with any history of wheeze or respiratory allergy.

Interactions

rs10208293 and rs1420101 are the two independent regulatory signals at the IL1RL1 locus. Their effects on sST2 are mechanistically distinct — carrying risk alleles at both represents a compounding of two separate derangements in the IL-33 alarm system. This is the interaction worth tracking in compound analysis.

Upstream, the IL33 gene⁸⁸ IL33 gene variant rs992969 determines how much IL-33 ligand is produced. A person carrying risk alleles at both IL33 (rs992969) and IL1RL1 (rs10208293) faces elevated ligand production meeting altered receptor regulation — a combined effect on the entire IL-33/ST2 signaling axis that neither variant predicts alone. The TSLP locus (rs1837253, rs3806933) acts upstream in the same Th2 pathway, and carriers of multiple allergy GWAS risk variants in this pathway have substantially higher cumulative risk than predicted by any single SNP.