Dataset Information

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

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 (? = -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.

SUBMITTER: Smith D

PROVIDER: S-EPMC5362243 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Smith Dirk D Helgason Hannes H Sulem Patrick P Bjornsdottir Unnur Steina US Lim Ai Ching AC Sveinbjornsson Gardar G Hasegawa Haruki H Brown Michael M Ketchem Randal R RR Gavala Monica M Garrett Logan L Jonasdottir Adalbjorg A Jonasdottir Aslaug A Sigurdsson Asgeir A Magnusson Olafur T OT Eyjolfsson Gudmundur I GI Olafsson Isleifur I Onundarson Pall Torfi PT Sigurdardottir Olof O Gislason David D Gislason Thorarinn T Ludviksson Bjorn Runar BR Ludviksdottir Dora D Boezen H Marike HM Heinzmann Andrea A Krueger Marcus M Porsbjerg Celeste C Ahluwalia Tarunveer S TS Waage Johannes J Backer Vibeke V Deichmann Klaus A KA Koppelman Gerard H GH Bønnelykke Klaus K Bisgaard Hans H Masson Gisli G Thorsteinsdottir Unnur U Gudbjartsson Daniel F DF Johnston James A JA Jonsdottir Ingileif I Stefansson Kari K

PLoS genetics 20170308 3

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 a ...[more]

PMID: 28273074

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Project description:PurposeCurrent understanding of the relationship between COPD phenotype and health care resource utilization (HCRU) is limited. This real-world study evaluated disease burden and HCRU for COPD subgroups prone to exacerbation as defined by blood eosinophil (EOS) count and multiple inhaler triple therapy (MITT) use.MethodsThis was a large-scale, retrospective, longitudinal, observational cohort study using data from the US IBM Watson Explorys real-world database (GSK Study HO-17-18395). The population of interest comprised patients with COPD ≥40 years of age with ≥2 moderate or ≥1 severe exacerbations (prior year) while on inhaled maintenance therapy, with ≥1 blood EOS count. Data were analyzed during the year prior to index date (last COPD encounter between January 1, 2011 and December 31, 2016). Four subgroups were analyzed based on a combination of EOS counts (<150 and ≥150 cells/μL) and MITT use (receiving or not receiving). Among these groups, clinical characteristics, exacerbations, and HCRU were described. A sensitivity analysis that further stratified EOS into four categories (<150, ≥150-<300, ≥300-<500, and ≥500 cells/μL) was also performed.ResultsThe COPD population of interest comprised 34,268 patients. Subgroups with EOS ≥150 cells/μL vs <150 cells/μL had more comorbidities and experienced significantly higher mean numbers of moderate exacerbations (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 1.93 vs 1.82, P<0.0001; receiving MITT 2.26 vs 2.16, P=0.0062) and COPD-related emergency visits (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 3.0 vs 2.5, P<0.001; receiving MITT 3.4 vs 3.1, P=0.0011). Increasing EOS category was associated with higher HCRU.ConclusionBlood EOS ≥150/μL cells were associated with increased HCRU and higher exacerbation rates compared with EOS <150 cells/μL, irrespective of MITT use. COPD phenotyping using blood EOS could help identify candidates for additional therapies that target eosinophilic inflammatory pathways.

Dataset Information

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Publications

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

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