rs3939286 — IL33 IL33 intronic asthma variant

Regulatory variant ~5 kb upstream of IL33; the T allele is associated with increased asthma susceptibility, hay fever, nasal polyps, and chronic rhinosinusitis across large GWAS meta-analyses, colocalising with the IL-33 expression locus in airway epithelium

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IL33 rs3939286 — A Second Alarmin Dial Upstream of the Asthma Signal

Five kilobases upstream of the interleukin-33 gene on chromosome 9, rs3939286 sits in the same regulatory neighbourhood as the well-characterised rs1342326 and rs992969 IL33 risk variants. IL-3311 IL-33
An alarmin cytokine released from airway epithelial cells upon damage, allergen exposure, or viral infection; it binds the ST2 receptor (encoded by IL1RL1) on mast cells, ILC2 innate lymphoid cells, and eosinophils, triggering the type-2 inflammatory cascade that drives asthma, allergic rhinitis, and atopic disease is one of the pivotal upstream activators of atopic inflammation. rs3939286 lies in the regulatory landscape that controls how much IL-33 is produced in response to environmental insults — and the T allele is consistently associated with increased susceptibility to asthma, hay fever, nasal polyps, and chronic rhinosinusitis across independent study populations.

The Mechanism

rs3939286 at chr9:6,210,099 (GRCh38) occupies a chromatin-accessible region roughly 5 kb upstream of the IL33 transcription start site. The T allele (the GRCh38 reference allele at this position, but the population minor allele at ~25% European frequency) is embedded in a regulatory zone densely populated with GWAS signals for atopic disease. The mechanistic basis closely parallels the nearby rs992969 eQTL variant: upstream regulatory variants in this region modulate transcription factor binding and enhancer activity22 transcription factor binding and enhancer activity
Such as OCT-1/POU2F1 binding to an enhancer-blocking element, demonstrated for neighbouring IL33 GWAS variants in Aneas et al., Nat Commun 2021, ultimately controlling IL-33 mRNA output in bronchial epithelium. The C allele — the common protective form at ~75% European frequency — represents the baseline regulatory configuration. T allele carriers show an expression profile associated with elevated IL-33 availability during allergen or viral challenge, amplifying the alarmin signal through the ST2 → ILC2 → eosinophil type-2 axis.

Because rs3939286 and rs1342326/rs992969 tag the same upstream regulatory domain but at distinct positions, they may represent partially independent regulatory effects that compound in carriers of multiple IL33 risk alleles across this locus.

The Evidence

The first published association33 first published association
Buysschaert et al. Allergy 2010; two-stage Belgian study; 284 nasal polyp patients and 427 controls across four hospitals identified rs3939286 as a susceptibility factor for nasal polyposis: the T allele (reported as "A-allele" on the older minus-strand convention) conferred OR 1.60 (95% CI 1.16–2.22) per allele in stage 1 and a combined OR of 1.53 (95% CI 1.21–1.96, p=0.00041). Combined risk assessment with the IL1RL1 variant rs1420101 further elevated nasal polyp risk, indicating that the full IL33/ST2 signalling axis contributes to NP pathogenesis.

In an Iranian asthma cohort (Matloubi et al. 202044 (Matloubi et al. 2020
126 asthmatics, 300 controls), homozygous T carriers showed OR 2.18 (95% CI 1.05–4.52) for asthma development, and the combined T/T + T/C genotype group showed OR 2.53 (95% CI 1.30–4.94) specifically for moderate and severe disease, suggesting a dose-response effect. The T allele preferentially associated with non-atopic and childhood-onset asthma subtypes in this study — a noteworthy contrast with some other IL33 variants, which lean toward atopic phenotypes.

The clearest evidence of a shared causal architecture comes from a Mendelian randomisation and colocalization study55 Mendelian randomisation and colocalization study
Tu et al. Sci Rep 2024 demonstrating that asthma and chronic rhinosinusitis share the same causal genetic variant at this locus (posterior probability PP.H4 = 0.99) — effectively establishing rs3939286 as the colocalising signal linking IL-33 pathway activation to both upper and lower airway inflammatory disease.

The GWAS Catalog records large-scale phenome-wide associations for this variant at extraordinary significance levels: asthma at p=2×10⁻⁶⁶, hay fever at p=7×10⁻¹⁷, and nasal polyps at p=7×10⁻¹⁵, with the C allele (risk allele frequency ~0.75) showing protective beta coefficients in all three traits. These signals rank rs3939286 among the most robustly replicated IL33 locus variants in all of respiratory allergy genetics.

Practical Implications

T allele carriers — approximately 42% of Europeans carry at least one T (CT or TT) — face elevated risk across the atopic triad of asthma, allergic rhinitis, and nasal polyposis. The same IL-33 upstream regulatory mechanism that predisposes to these conditions also underlies susceptibility to chronic rhinosinusitis, creating a genetically coherent upper-lower airway disease trajectory. Monitoring biomarkers of IL-33/type-2 axis activity — fractional exhaled nitric oxide (FeNO) and peripheral blood eosinophil count — provides a quantitative readout of how active the downstream pathway is. Biologics targeting IL-33 (itepekimab) or the upstream alarmin cascade (tezepelumab, anti-TSLP) are mechanistically well-matched to this variant's pathophysiology when disease is moderate to severe and uncontrolled.

Interactions

rs3939286 shares its upstream regulatory territory with rs992969 (~400 bp upstream) and rs1342326 (~25 kb upstream) — both IL33 expression-associated GWAS variants. Carriers of multiple IL33 upstream risk alleles may face additive IL-33 expression burden, as each variant tags a distinct position in the regulatory domain controlling IL-33 output. The IL1RL1/ST2 receptor variant rs1420101 (T allele, reduced soluble ST2 decoy production) compounds with IL33 upstream risk alleles by simultaneously increasing IL-33 ligand availability and reducing IL-33 buffering via the decoy receptor — a compounding interaction along both arms of the IL-33/ST2 signalling axis.

Drug Interactions

itepekimab reduced_efficacy literature
tezepelumab reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Standard IL-33 Output Normal

Common form with baseline IL-33 upstream regulatory activity and population-average asthma risk

You carry two copies of the C allele at rs3939286, the most common genotype in European populations (approximately 48% of individuals). The C allele represents the baseline regulatory configuration at this IL33 upstream position — your IL-33 expression in bronchial epithelium is at population-average levels, and your risk for asthma, hay fever, and nasal polyposis from this variant is not elevated above baseline. The C allele is the population major form in Europeans (~75% frequency) and East Asians (~96% frequency).

CT Elevated IL-33 Signalling Risk Intermediate

One copy of the IL-33 upstream risk allele with moderately elevated asthma and rhinitis susceptibility

rs3939286 is located approximately 5 kb upstream of the IL33 gene in a regulatory region associated with IL-33 expression levels in bronchial epithelium. The T allele tags a haplotype associated with increased IL-33 availability during tissue-damage signals (allergen, virus, pollutant). As a heterozygote, one copy of your IL33 upstream region carries the risk haplotype — producing an intermediate increase in IL-33 output compared to CC homozygotes, which translates to a moderately heightened IL-33 → ST2 → ILC2 → eosinophil type-2 axis. This axis drives the eosinophilic airway inflammation underlying atopic asthma, allergic rhinitis, and nasal polyp formation. The colocalisation of asthma and chronic rhinosinusitis at this locus (PP.H4 = 0.99) means risk is coherent across upper and lower airway compartments.

TT High IL-33 Signalling Risk High Risk

Two copies of the IL-33 upstream risk allele — highest expression-associated genotype with substantially elevated asthma, nasal polyp, and chronic rhinosinusitis risk

As a TT homozygote, you carry the highest possible dose of the IL33 upstream risk haplotype. Both copies of the IL33 upstream regulatory region at chr9:6,210,099 are in the T-allele configuration, meaning every IL-33 induction event — allergen exposure, respiratory virus, airborne pollutant, or tissue damage — generates the maximal upstream regulatory signal for IL-33 expression. The downstream consequences are chronic priming of the ST2 → ILC2 → eosinophil axis: elevated blood eosinophil counts, heightened FeNO, and a type-2 high airway inflammatory profile that predisposes to eosinophilic asthma, nasal polyposis with eosinophilic chronic rhinosinusitis (eCRS), and hay fever. The colocalization of asthma and CRS at this locus (PP.H4 = 0.99, PMID 39455747) makes TT homozygotes biologically at risk for the full upper-lower airway inflammatory triad. From a therapeutic standpoint, this genotype is among those most likely to benefit from biologic therapy targeting IL-33 (itepekimab) or the broader upstream alarmin cascade (tezepelumab) when asthma or CRS with nasal polyps is moderate-to-severe and inadequately controlled by standard inhaled therapy.