rs146597587 — IL33

IL33 Splice Variant — The Natural Asthma Shield in Your Genome

Every day your airways face pollutants, allergens, and viruses. When epithelial cells lining the lung are damaged, they release an alarmin called IL-33 (interleukin-33)¹¹ IL-33 (interleukin-33)
An alarmin cytokine stored in the nuclei of epithelial cells and released upon tissue damage; it activates the immune system via the ST2 receptor on mast cells, ILC2s (group 2 innate lymphoid cells), eosinophils, and Th2 cells, driving the type 2 inflammatory response responsible for allergic asthma. IL-33 is a key initiator of the cascade that culminates in airway narrowing, mucus hypersecretion, and the eosinophilic inflammation that defines most asthma. A small fraction of people in European populations carry a rare variant in the IL33 gene — rs146597587-C — that essentially disables this alarmin and dramatically reduces their susceptibility to asthma and allergic airway disease.

The Mechanism

The rs146597587 variant disrupts a canonical splice acceptor site²² splice acceptor site
A splice acceptor is the AG dinucleotide at the 3' end of an intron; the spliceosome recognises this signal to cut the intron out and join the flanking exons together into mature mRNA. Disrupting it prevents normal splicing at the boundary of the last intron and the final coding exon (exon 7) of the IL33 transcript. When the C allele is present, the spliceosome fails to recognise the splice site, and approximately half of IL33 transcripts in a heterozygous carrier retain the last intron. That intron contains a premature stop codon, so the retained-intron mRNA is translated into a truncated protein — IL-33(1–204) — that is 66 amino acids shorter than the full-length IL-33(1–270).

The truncated protein is not simply a weak version of IL-33: it has entirely normal intracellular localisation but cannot bind the IL-33 receptor ST2³³ cannot bind the IL-33 receptor ST2
ST2 (also called IL-1RL1) is the cell-surface receptor for IL-33; binding triggers the MyD88 signalling cascade and NF-κB activation that drives inflammatory gene expression in mast cells, ILC2s, and eosinophils and fails to activate ST2-expressing cells. The C allele therefore functions as a true loss-of-function allele, and heterozygous carriers show approximately 40% lower total IL33 mRNA⁴⁴ 40% lower total IL33 mRNA
The retained-intron transcripts are subject to nonsense-mediated mRNA decay, reducing the pool of functional message compared to non-carriers — a direct readout of the haploinsufficiency effect.

The Evidence

The foundational study was conducted by Smith et al. 2017⁵⁵ Smith et al. 2017
A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. PLoS Genetics, March 2017. Primary analysis in the Icelandic whole-genome-sequenced cohort; replication across European populations. The team identified rs146597587-C at a frequency of 0.65% in the Icelandic population and replicated it across European cohorts. The protective effect on asthma was striking: OR = 0.47 (95% CI 0.32–0.70, P = 1.8×10⁻⁴) in 6,465 cases and 302,977 controls. Heterozygous carriers of the C allele had more than half the asthma risk of non-carriers. On eosinophils — a key effector cell in allergic inflammation — the effect was even more statistically dramatic: β = −0.21 SD (P = 2.5×10⁻¹⁶) in 103,104 individuals, confirming that reducing IL-33 output directly dampens eosinophilic inflammation.

Independent replication came from the Blood-Cell Consortium (Mousas et al. 2017)⁶⁶ Blood-Cell Consortium (Mousas et al. 2017)
Rare coding variants pinpoint genes that control human hematological traits. PLoS Genetics, August 2017. Analysed 137,086 rare variants across 308,572 participants and 15 haematological traits, which found rs146597587 associated with reduced eosinophil count at P = 2.4×10⁻²³ — ten orders of magnitude beyond genome-wide significance. That study also independently confirmed the asthma protection (OR 0.56, P = 2.6×10⁻⁷) and extended the finding to allergic rhinitis (OR 0.55, P = 4.2×10⁻⁴), demonstrating that the protective effect spans the full spectrum of type-2 allergic disease.

At a population level, the variant's rarity (C allele frequency ~0.4% in Europeans, effectively absent in African and South Asian populations) means it contributes minimally to population-level asthma variance — but for the individual carrier, the protection is large and mechanistically certain. The UK Biobank pLOF analysis (Emdin et al. 2018)⁷⁷ UK Biobank pLOF analysis (Emdin et al. 2018)
Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nature Communications 2018; >400,000 UK Biobank participants confirmed IL33 pLOF variants among a select group of genetic variants that protect against asthma and allergic disease across the largest biobank dataset available at the time.

The mechanism is directly therapeutically validated: the anti-IL-33 monoclonal antibody itepekimab (which pharmacologically mimics what this variant does genetically) demonstrated in a Phase 3 trial (Wechsler et al. 2021)⁸⁸ (Wechsler et al. 2021)
Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma. NEJM 2021 a 53% reduction in asthma-control-loss events (OR 0.42) and significant eosinophil reduction. This drug-genetics convergence is among the clearest validations in respiratory immunology: the same pathway disrupted by this natural variant is the target of a clinically approved treatment.

Practical Implications

For C allele carriers, the primary implication is genuine biological protection against type-2 driven asthma and allergic airway disease. This is not a statistical approximation — the mechanism is completely characterised and directly validated by therapeutic evidence. The protection is most clinically meaningful in the context of other asthma risk factors: individuals who are C allele carriers but have significant allergen exposure, smoking history, or other genetic susceptibility factors may still develop asthma, though at meaningfully reduced rates.

Because eosinophil counts are reliably lower in C allele carriers (not merely during attacks but as a baseline haematological trait), clinicians interpreting blood counts in heterozygous individuals should be aware that a "low-normal" eosinophil count may reflect this variant rather than an underlying deficiency.

Interactions

The IL-33/ST2 signalling axis interacts with several other innate immune pathways. The TSLP (thymic stromal lymphopoietin) alarmin, encoded by TSLP and regulated by variants including rs1837253, amplifies ILC2 activation in parallel with IL-33. Individuals with high-TSLP variants may have attenuated benefit from the IL33 protective allele, since TSLP can activate ILC2s even without IL-33. Similarly, IL-1RL1 (ST2) variants including rs992969 affect receptor expression levels and may modify the downstream consequences of reduced IL-33 output. The GWAS Catalog records strong associations at the IL33 locus (rs1420101 as the common sentinel GWAS SNP for asthma risk) that are independent of rs146597587 and reflect different regulatory variants in the same gene.