title: 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 (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.
authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
authors.forename: Dirk
authors.initials: D
authors.lastname: Smith
authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Hannes
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authors.lastname: Helgason
authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.affiliation: Department of Medicine, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Unnur Steina
authors.initials: US
authors.lastname: Bjornsdottir
authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
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authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.
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authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
authors.forename: Haruki
authors.identifier: 0000-0002-3464-4715
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authors.lastname: Hasegawa
authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
authors.forename: Michael
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authors.lastname: Brown
authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
authors.forename: Randal R
authors.identifier: 0000-0002-7821-2682
authors.initials: RR
authors.lastname: Ketchem
authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
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authors.identifier: 0000-0002-7475-3393
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authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
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authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.
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authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.
authors.forename: Aslaug
authors.initials: A
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authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.
authors.forename: Asgeir
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authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.
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authors.affiliation: The Laboratory in Mjodd, RAM, Reykjavik, Iceland.
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authors.initials: GI
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authors.affiliation: Department of Clinical Biochemistry, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Isleifur
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authors.affiliation: Laboratory Hematology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Pall Torfi
authors.initials: PT
authors.lastname: Onundarson
authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
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authors.initials: O
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authors.affiliation: Department of Respiratory Medicine and Sleep, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
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authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Respiratory Medicine and Sleep, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Thorarinn
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authors.lastname: Gislason
authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Bjorn Runar
authors.initials: BR
authors.lastname: Ludviksson
authors.affiliation: Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Respiratory Medicine and Sleep, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Dora
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authors.lastname: Ludviksdottir
authors.affiliation: GRIAC research institute, Groningen, The Netherlands.|University Medical Center Groningen, University of Groningen, Department of Epidemiology, Groningen, The Netherlands.
authors.forename: H Marike
authors.initials: HM
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authors.affiliation: Center for Pediatrics, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
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authors.initials: A
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authors.affiliation: Center for Pediatrics, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Marcus
authors.identifier: 0000-0003-2008-4582
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authors.affiliation: Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen University, Copenhagen, Denmark.
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authors.affiliation: COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
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authors.identifier: 0000-0002-7464-3354
authors.initials: TS
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authors.affiliation: COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
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authors.initials: J
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authors.affiliation: Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen University, Copenhagen, Denmark.
authors.forename: Vibeke
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authors.affiliation: Center for Pediatrics, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Klaus A
authors.initials: KA
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authors.affiliation: GRIAC research institute, Groningen, The Netherlands.|University Medical Center Groningen, University of Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands.
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authors.identifier: 0000-0001-8567-3252
authors.initials: GH
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authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
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authors.identifier: 0000-0002-7049-2827
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authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
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authors.affiliation: Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
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authors.lastname: Johnston
authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.|Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Ingileif
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authors.lastname: Jonsdottir
authors.affiliation: deCODE genetics / Amgen Inc., Reykjavík, Iceland.|Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000818:Animals; D001249:Asthma / Q000235:genetics*; D001665:Binding Sites; D001681:Biological Assay; D002648:Child; D002675:Child, Preschool; D003718:Denmark; D004804:Eosinophils / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007055:Iceland; D007223:Infant; D007231:Infant, Newborn; D000067596:Interleukin-33 / Q000235:genetics*; D007438:Introns; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D055815:Young Adult
chemical_list: C506536:IL33 protein, human; C506535:Il33 protein, mouse; D000067596:Interleukin-33