rs1342326 — IL33 IL33 regulatory variant

Regulatory variant upstream of IL33; the C allele elevates IL-33 expression, amplifying the alarmin signal through the ST2 receptor and raising susceptibility to asthma, allergic rhinitis, hay fever, and eosinophilic airway inflammation

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IL33 rs1342326 — When the Alarmin Dial Is Turned Up

Beneath the surface of allergic asthma, rhinitis, and eczema lies a shared distress signal: IL-3311 IL-33
Interleukin-33, an alarmin cytokine stored in the nuclei of epithelial cells lining the airways, gut, and skin; released upon cell damage or allergen exposure, it binds the ST2 (IL1RL1) receptor on mast cells, ILC2 innate lymphoid cells, and eosinophils to initiate type-2 inflammation. rs1342326 sits approximately 25 kilobases upstream of the IL33 transcription start site on chromosome 9. The C allele acts as a gain-of-expression variant: carriers produce more IL-33 mRNA in bronchial epithelium, meaning every allergen challenge, viral rhinitis, or pollutant exposure generates a louder alarm. The GABRIEL consortium's genome-wide association study22 GABRIEL consortium's genome-wide association study
Moffatt et al. 2010, N=26,475; p=9×10⁻¹⁰ first established this SNP at genome-wide significance for asthma risk, and it has since been replicated across multiple European, Middle Eastern, and pediatric cohorts for asthma, allergic rhinitis, and hay fever.

The Mechanism

rs1342326 is a regulatory (eQTL) variant33 regulatory (eQTL) variant
Expression quantitative trait locus — a variant that influences how much RNA is made from a nearby gene, without changing the protein sequence in the IL33 upstream regulatory region. The C allele is associated with measurably higher serum IL-33 protein concentrations in carriers, confirmed in the Tunisian pediatric cohort (Charrad et al. 2018)44 (Charrad et al. 2018)
PMID 28985997. Higher constitutive IL-33 output means that the ST2/IL1RL1 receptor system — which mediates type-2 immune activation on mast cells, ILC2s, and eosinophils — is chronically primed above population baseline.

A second immune mechanism emerges from the PASTURE/EFRAIM birth cohort: C allele carriers show significantly reduced regulatory T cells (Tregs)55 regulatory T cells (Tregs)
CD4+CD25+FOXP3+ cells that suppress immune overactivation; lower Treg frequency is associated with impaired allergen tolerance and higher atopic disease risk and elevated SOCS3 mRNA expression, which negatively correlates with Treg abundance (Schröder et al. 2016). This suggests that the rs1342326-C allele not only increases IL-33 output but also undermines the immune regulatory circuitry that normally limits Th2 responses — a compounding effect that helps explain the variant's association with multiple atopic phenotypes simultaneously.

The Evidence

The landmark GABRIEL GWAS66 GABRIEL GWAS
Moffatt et al. NEJM 2010; 10,365 cases + 16,110 controls from European populations; genome-wide significance p=9×10⁻¹⁰ placed rs1342326 at the IL33 locus as one of the reproducible asthma risk signals, alongside IL1RL1 (ST2 receptor), HLA-DQ, and ORMDL3/GSDMB. The C allele risk allele frequency of ~16% in Europeans means a substantial fraction of the population carries at least one copy.

Pediatric longitudinal data strengthens the causal interpretation. In the Finnish post-bronchiolitis cohort77 post-bronchiolitis cohort
Korppi et al. Acta Paediatr 2020; 141 children followed to ages 6 and 12, AC/CC carriers showed OR 2.17 for allergic rhinitis at age 6.4, rising to OR 3.23 at age 11.7 — a signal that strengthens over time, consistent with the progressive nature of atopic march. Notably, 22.5% of variant carriers required inhaled corticosteroids by age 6 versus only 8.9% of AA homozygotes.

In an Iranian adult case-control study (Matloubi et al. 202088 (Matloubi et al. 2020
126 asthmatics + 300 controls), the CC genotype carried OR 2.50 (95% CI 1.33–4.69) for asthma and was specifically associated with the atopic, eosinophil-elevated subtype. The elevated peripheral eosinophil counts in CC carriers confirm that the IL33-C eQTL effect flows through the IL-33→ST2→eosinophil axis, producing the quantitative biomarker signature consistent with type-2 high asthma.

An important pharmacogenomic signal comes from a Canadian pediatric exacerbation study99 Canadian pediatric exacerbation study
Tse et al. Pediatr Pulmonol 2019; 491 children with acute moderate-to-severe asthma exacerbations: C allele carriers experienced significantly worse acute outcomes (management failure OR 0.52 for AA vs other genotypes), with higher rates of hospitalization and prolonged emergency care — suggesting that elevated IL-33 signaling during acute viral triggers drives more severe exacerbation phenotypes that are harder to control acutely.

Practical Implications

The C allele's mechanism — elevated IL-33 output → chronically primed ST2/eosinophil axis — points to two monitoring priorities: (1) tracking the downstream eosinophil and airway inflammation burden with FeNO and blood eosinophil count, and (2) being alert to the atopic march trajectory, particularly after early-life respiratory infections. IL-33 itself is now a pharmaceutical target: itepekimab (Dupixent's companion anti-IL-33 antibody) and tezepelumab (anti-TSLP, which synergises with IL-33 upstream) both mechanistically converge on the pathway amplified by this variant. Carriers with moderate-to-severe asthma are biologically well-matched to biologics that interrupt upstream type-2 signaling.

Interactions

rs1342326 (IL33 ligand, elevated expression) and rs1420101 (IL1RL1/ST2 receptor, reduced sST2 decoy expression) represent two nodes of the same IL-33 signaling axis. The rs1420101-T allele lowers circulating soluble ST2 — the natural IL-33 decoy receptor — so IL-33 is less buffered. Carrying C at rs1342326 and T at rs1420101 compounds both ends: more IL-33 released AND less decoy to intercept it. This interaction is documented in the literature on the IL-33/ST2 pathway and is captured in compound actions in this database. The related IL33 variant rs992969 tags a second upstream regulatory position also associated with increased IL33 expression; compound carriers of both IL33 risk alleles carry additive expression burden.

Drug Interactions

itepekimab reduced_efficacy literature
tezepelumab reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard IL-33 Output Normal

Common form with baseline IL-33 expression and typical asthma and allergy risk

You carry two copies of the A (reference) allele at rs1342326, the most common genotype in European populations (~70% of individuals). Your IL-33 expression in bronchial epithelium is at population-average levels, and your risk for asthma, allergic rhinitis, and hay fever from this specific variant is not elevated above baseline. The A allele is the ancestral form globally; the IL33 regulatory signal at this position does not alter your type-2 immune tone.

AC Elevated IL-33 Activity Intermediate

One C allele increasing IL-33 expression with moderately elevated asthma and allergic rhinitis risk

IL-33 is released from epithelial cells in the airways and skin during tissue damage, allergen exposure, and viral infection. As an eQTL variant, rs1342326-C elevates IL-33 mRNA levels in bronchial epithelium, increasing the amount of IL-33 available to bind ST2 receptors on mast cells, ILC2 innate lymphoid cells, and eosinophils. Heterozygotes produce intermediate amounts — one risk allele contributing to the elevated expression. Additionally, C allele carriers show reduced regulatory T cell (Treg) abundance and elevated SOCS3 expression in childhood, suggesting impaired immune tolerance as a parallel mechanism. This combination — more IL-33 ligand and less immune regulation — underlies the moderate elevation in allergic disease risk observed in AC heterozygotes.

CC High IL-33 Activity High Risk

Two C alleles with highest IL-33 expression and substantially elevated asthma and allergic rhinitis risk, including more severe exacerbation phenotype

Both copies of your IL33 regulatory region carry the expression-amplifying C allele. Every unit of IL-33-releasing stimulus — viral rhinitis, allergen inhalation, pollutant exposure, or airway mechanical stress — drives more IL-33 secretion from your bronchial epithelium than in AA or AC individuals. The downstream consequences are measurable: elevated peripheral blood eosinophil counts, greater eosinophilic airway inflammation (higher FeNO), and a clinical phenotype that aligns with the type-2-high asthma endotype targeted by modern biologics. A Finnish longitudinal study found that variant carriers who had bronchiolitis in infancy showed progressively higher allergic rhinitis risk into adolescence — consistent with the atopic march driven by chronic IL-33 signaling elevation. In acute settings, the pediatric exacerbation data suggests your IL-33 genotype predicts worse responses to standard bronchodilator therapy during exacerbations, which is mechanistically consistent: bronchodilators address airway narrowing but not the underlying eosinophilic cytokine cascade.