ArticlePLoS genetics2017
A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 4 of them syntheses that pooled it.
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Who cites it
78 citing papers in PubMed, 4 syntheses or guidelines pooled it, 141 citations in OpenAlex.
- Genetic variants associated with platelet count are predictive of human disease and physiological markers.Communications biology · 2021Pooled it
- Role of the IL-33/ST2 axis in cardiovascular disease: A systematic review and meta-analysis.PloS one · 2021Pooled it
- Systematic Review on the Efficacy and Safety of Oral Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis.Frontiers in medicine · 2021Pooled it
- Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.Nature communications · 2020Pooled it
- Genome-wide burden and association analyses implicate copy number variations in asthma risk among children and young adults from Latin America.Scientific reports · 2018Trial
- Structural and functional consequences of IL33 and IL1RL1 coding variants on IL-33/ST2 signaling.Genes and immunity · 2026Article
- Interleukin-33 and its receptor: multifaceted roles and emerging therapeutic potential.Nature reviews. Immunology · 2026Review
- From Susceptibility to Severity: The Impact of Interleukin-33 rs1929992 Polymorphism on Asthma in a Taiwanese Population.Life (Basel, Switzerland) · 2026Article
- Mechanisms and therapeutic strategies of asthma: from bench to bedside.Signal transduction and targeted therapy · 2026Review
- IL-33 blockade in asthma: a story of hype, hope and hindsight.ERJ open research · 2026Article
- FRONTIER-3: a randomised phase 2a study to investigate tozorakimab, an anti-interleukin-33 monoclonal antibody, in early-onset asthma.ERJ open research · 2026Article
- Boosting the Power of Rare Variant Association Studies by Imputation Using Large-scale Sequencing Population.Genomics, proteomics & bioinformatics · 2025Article
- Where eye meets body part 2: uniting allergy pathways in ocular and atopic disease - T cells take the lead.Current opinion in allergy and clinical immunology · 2025Review
- A map of blood regulatory variation in South Africans enables GWAS interpretation.Nature genetics · 2025Article
- Targeting alarmins in asthma: From bench to clinic.The Journal of allergy and clinical immunology · 2025Review
- Long-term alterations in lung epithelial cells after EL-RSV infection exacerbate allergic responses through IL-1β-induced pathways.Mucosal immunology · 2024Article
- Genetics of chronic respiratory disease.Nature reviews. Genetics · 2024Review
- Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease.Kidney international reports · 2024Article
- Female-specific enhancement of eosinophil recruitment and activation in a type 2 innate inflammation model in the lung.Clinical and experimental immunology · 2024Article
- Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.The Journal of allergy and clinical immunology · 2024Article
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
40 authors at 8 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.