rs13424006 — IL1RL1

IL1RL1 (ST2) — A Protective Variant in the IL-33 Alarm Circuit

The IL1RL1 gene¹¹ IL1RL1 gene
Interleukin-1 Receptor-Like 1, encoding the ST2 protein — the primary cell-surface receptor for the alarmin cytokine IL-33, expressed on mast cells, eosinophils, ILC2s, and Th2 lymphocytes is one of the most replicated loci in allergy and asthma genetics. Most research focuses on variants that increase risk. rs13424006 is notable for the opposite reason: the C allele at this intronic position is protective — carriers have a measurably lower risk of developing late-onset wheeze, the wheezing phenotype most strongly linked to persistent adult asthma.

The IL-33/ST2 axis functions as an epithelial damage alarm. When airway cells are injured by viruses, allergens, or pollutants, they release IL-33²² IL-33
A nuclear alarmin cytokine that, when released from damaged epithelial cells, binds to ST2 on ILC2s, mast cells, and eosinophils, triggering a rapid Th2 cascade. The intensity of that alarm depends on the ratio between membrane-bound ST2 (which transmits the signal) and soluble sST2 (which mops up free IL-33 before it can reach its target cells). IL1RL1 variants modulate this ratio — some increasing signalling capacity, others buffering it. rs13424006 sits in the intron where this regulatory balance is calibrated.

The Mechanism

rs13424006 maps to position 102,350,776 on chromosome 2 (GRCh38), within the 10th intron of IL1RL1. Like rs10208293 — the other intronic IL1RL1 variant that specifically tags late-onset wheeze in the same study — rs13424006 is presumed to act through an eQTL mechanism, influencing the relative production of membrane-bound IL1RL1 and the soluble decoy sST2 without altering the protein sequence. The C allele tags a haplotype associated with more effective IL-33 buffering: greater production or activity of sST2, which intercepts IL-33 before it activates eosinophils and ILC2s.

rs13424006 and rs10208293 both sit in the 10th intron and both specifically associate with the late-onset wheeze phenotype, but they are genotyped separately and may tag distinct regulatory elements within the same intronic region. Whether their effects are additive, redundant, or mechanistically coupled is not yet established.

The Evidence

The protective effect of the C allele was first defined in a large two-cohort study by Savenije et al. (2014)³³ Savenije et al. (2014), which meta-analysed data from 2,007 children in the Dutch PIAMA cohort and 7,247 children in the UK ALSPAC cohort, following wheeze phenotypes from birth to age 8. The analysis distinguished four phenotypes: no wheeze, early-transient wheeze, intermediate-onset, and late-onset wheeze. rs13424006 was one of only two IL1RL1 SNPs that associated specifically with late-onset wheeze (OR approximately 0.74, 95% CI 0.63–0.87), meaning C allele carriers develop this phenotype at substantially lower rates than TT homozygotes.

The late-onset specificity is clinically important. Late-onset wheeze — wheeze that develops after the toddler years, typically in mid-childhood — has a much stronger association with persistent adult asthma than early-transient wheeze, which is largely virus-driven and often resolves. The IL-33/ST2 pathway specifically drives the eosinophilic subtype⁴⁴ eosinophilic subtype
Eosinophilic asthma is characterised by airway eosinophilia, elevated FeNO, and good response to inhaled corticosteroids and IL-5/IL-13 pathway biologics of asthma that underlies most late-onset disease.

Confirmation came from Chinese Han children (265 asthma cases, 153 controls) in Wu et al. (2021)⁵⁵ Wu et al. (2021), where CT or CC genotypes were associated with lower asthma susceptibility (adjusted OR 0.584, 95% CI 0.362–0.941, p=0.027) and, in those with asthma, a lower probability of elevated FeNO at baseline (adjusted OR 0.286, 95% CI 0.125–0.652, p=0.003). The FeNO finding directly connects genotype to eosinophilic airway inflammation — the mechanism the IL-33/ST2 axis drives.

Fourteen years of IL1RL1 population genetics, most recently summarised in Savenije et al. (2011)⁶⁶ Savenije et al. (2011), established that 13 of 15 IL1RL1 SNPs tested were significantly associated with circulating sST2 levels in childhood, confirming the IL1RL1 locus as the primary genetic determinant of the soluble decoy receptor that buffers IL-33 signalling.

Practical Implications

For TT homozygotes, the actionable priority is awareness and monitoring. The TT genotype represents the population baseline — lacking the extra sST2-buffering effect the C allele confers. This does not mean TT individuals are at elevated risk in an absolute sense; it means they do not carry the C allele's protective advantage. If there is any history of childhood wheeze, asthma, or respiratory allergy, checking FeNO is the highest-yield approach to characterise whether eosinophilic airway inflammation is present — and whether eosinophil-targeting treatments (ICS, dupilumab, mepolizumab, benralizumab, itepekimab) would be particularly well-matched.

For CC homozygotes, the protective genotype reduces eosinophilic airway inflammation risk through this particular regulatory element — but this doesn't override other asthma risk factors and shouldn't be interpreted as blanket protection against all respiratory allergy.

Interactions

rs13424006 and rs10208293 both tag the late-onset wheeze phenotype at the IL1RL1 locus, sitting in the same intronic region (10th intron). Their effects may reflect distinct regulatory elements — having the protective C allele at rs13424006 alongside a risk allele at rs10208293 may represent partial compensation rather than full protection.

The IL-33 ligand variant rs992969 determines how much IL-33 is produced upstream. A TT carrier at rs13424006 who also carries the IL-33 production-increasing allele at rs992969 faces elevated ligand meeting reduced buffering — a combined effect on the entire axis. The TSLP variant rs1837253 acts upstream in the same Th2 cascade; multiple risk alleles in this pathway produce substantially higher cumulative eosinophilic inflammation risk than any single SNP predicts.