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dc.contributor.authorSmith, Dirk
dc.contributor.authorHelgason, Hannes
dc.contributor.authorSulem, Patrick
dc.contributor.authorBjornsdottir, Unnur Steina
dc.contributor.authorLim, Ai Ching
dc.contributor.authorSveinbjornsson, Gardar
dc.contributor.authorHasegawa, Haruki
dc.contributor.authorBrown, Michael
dc.contributor.authorKetchem, Randal R
dc.contributor.authorGavala, Monica
dc.contributor.authorGarrett, Logan
dc.contributor.authorJonasdottir, Adalbjorg
dc.contributor.authorJonasdottir, Aslaug
dc.contributor.authorSigurdsson, Asgeir
dc.contributor.authorMagnusson, Olafur T
dc.contributor.authorEyjolfsson, Gudmundur I
dc.contributor.authorOlafsson, Isleifur
dc.contributor.authorOnundarson, Pall Torfi
dc.contributor.authorSigurdardottir, Olof
dc.contributor.authorGislason, David
dc.contributor.authorGislason, Thorarinn
dc.contributor.authorLudviksson, Bjorn Runar
dc.contributor.authorLudviksdottir, Dora
dc.contributor.authorBoezen, H Marike
dc.contributor.authorHeinzmann, Andrea
dc.contributor.authorKrueger, Marcus
dc.contributor.authorPorsbjerg, Celeste
dc.contributor.authorAhluwalia, Tarunveer S
dc.contributor.authorWaage, Johannes
dc.contributor.authorBacker, Vibeke
dc.contributor.authorDeichmann, Klaus A
dc.contributor.authorKoppelman, Gerard H
dc.contributor.authorBønnelykke, Klaus
dc.contributor.authorBisgaard, Hans
dc.contributor.authorMasson, Gisli
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorGudbjartsson, Daniel F
dc.contributor.authorJohnston, James A
dc.contributor.authorJonsdottir, Ingileif
dc.contributor.authorStefansson, Kari
dc.date.accessioned2017-05-15T10:48:41Z
dc.date.available2017-05-15T10:48:41Z
dc.date.issued2017-03
dc.identifier.citationA rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. 2017, 13 (3):e1006659 PLoS Genet.en
dc.identifier.issn1553-7404
dc.identifier.pmid28273074
dc.identifier.doi10.1371/journal.pgen.1006659
dc.identifier.urihttp://hdl.handle.net/2336/620186
dc.descriptionEfst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnen
dc.description.abstractIL-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.
dc.description.sponsorshipNetherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmarken
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.relation.urlhttp://journals.plos.org/plosgenetics/article/file?rev=2&id=10.1371/journal.pgen.1006659&type=printableen
dc.rightsArchived with thanks to PLoS geneticsen
dc.subjectPrótínen
dc.subjectAsmaen
dc.subjectSýtókínen
dc.subjectLyfen
dc.subjectMAB12en
dc.subjectHEM12en
dc.subjectPAD12en
dc.subjectAAI12en
dc.subject.meshInterleukin-33en
dc.subject.meshAsthmaen
dc.titleA rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.en
dc.typeArticleen
dc.contributor.department[ 1 ] Amgen Inc, Discovery Res, San Francisco, CA USA [ 2 ] Amgen Inc, DeCODE genet, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 3 ] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland [ 4 ] Natl Univ Hosp Iceland, Dept Med, Landspitali, Reykjavik, Iceland [ 5 ] RAM, Lab Mjodd, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 6 ] Natl Univ Hosp Iceland, Dept Clin Biochem, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 7 ] Natl Univ Hosp Iceland, Hematol Lab, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 8 ] Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland [ 9 ] Akureyri Hosp, Dept Clin Biochem, Akureyri, Iceland [ 10 ] Natl Univ Hosp Iceland, Dept Resp Med & Sleep, Landspitali, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 11 ] Natl Univ Hosp Iceland, Dept Immunol, Reykjavik, Iceland [ 12 ] GRIAC Res Inst, Groningen, Netherlands Show the Organization-Enhanced name(s) [ 13 ] Univ Med Ctr Groningen, Univ Groningen, Dept Epidemiol, Groningen, Netherlands Show the Organization-Enhanced name(s) [ 14 ] Univ Freiburg, Med Ctr, Ctr Pediat, Dept Gen Pediat Adolescent Med & Neonatol, Freiburg, Germany Show the Organization-Enhanced name(s) [ 15 ] Univ Copenhagen, Bispebjerg Univ Hosp, Dept Resp Med, Copenhagen, Denmark Show the Organization-Enhanced name(s) [ 16 ] Univ Copenhagen, Herlev & Gentofte Hosp, COPSAC, Copenhagen, Denmark Show the Organization-Enhanced name(s) [ 17 ] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Dept Pediat Pulmonol & Pediat Allergol, Groningen, Netherlandsen
dc.identifier.journalPLoS geneticsen
dc.rights.accessOpen Access - Opinn aðganguren
refterms.dateFOA2018-09-12T16:35:35Z
html.description.abstractIL-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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