دورية أكاديمية
A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma
| العنوان: | A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma |
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| المؤلفون: | Smith, Dirk, Helgason, Hannes, Sulem, Patrick, Bjornsdottir, Unnur Steina, Lim, Ai Ching, Sveinbjornsson, Gardar, Hasegawa, Haruki, Brown, Michael, Ketchem, Randal R., Gavala, Monica, Garrett, Logan, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Sigurdsson, Asgeir, Magnusson, Olafur T., Eyjolfsson, Gudmundur I., Olafsson, Isleifur, Onundarson, Pall Torfi, Sigurdardottir, Olof, Gislason, David, Gislason, Thorarinn, Ludviksson, Bjorn Runar, Ludviksdottir, Dora, Boezen, H. Marike, Heinzmann, Andrea, Krueger, Marcus, Porsbjerg, Celeste, Ahluwalia, Tarunveer S., Waage, Johannes, Backer, Vibeke, Deichmann, Klaus A., Koppelman, Gerard H., Bonnelykke, Klaus, Bisgaard, Hans, Masson, Gisli, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F., Johnston, James A., Jonsdottir, Ingileif, Stefansson, Kari |
| المصدر: | Smith , D , Helgason , H , Sulem , P , Bjornsdottir , U S , Lim , A C , Sveinbjornsson , G , Hasegawa , H , Brown , M , Ketchem , R R , Gavala , M , Garrett , L , Jonasdottir , A , Jonasdottir , A , Sigurdsson , A , Magnusson , O T , Eyjolfsson , G I , Olafsson , I , Onundarson , P T , Sigurdardottir , O , Gislason , D , Gislason , T , Ludviksson , B R , Ludviksdottir , D , .... |
| سنة النشر: | 2017 |
| المجموعة: | University of Groningen research database |
| مصطلحات موضوعية: | GENOME-WIDE ASSOCIATION, AIRWAY INFLAMMATION, GENETIC-VARIATION, LARGE-SCALE, IL-33, ST2, VARIANTS, RECEPTOR, POLYMORPHISMS, POPULATION |
| الوصف: | 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- Cassociates with lower eosinophil counts (beta= -0.21 SD, P = 2.5x10(-16), N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95% CI: 0.32, 0.70, P = 1.8x10(-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 ST2expressing 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://research.rug.nl/en/publications/cbb66b9e-bd67-435c-806f-7f301357232fTest |
| DOI: | 10.1371/journal.pgen.1006659 |
| الإتاحة: | https://doi.org/10.1371/journal.pgen.1006659Test https://hdl.handle.net/11370/cbb66b9e-bd67-435c-806f-7f301357232fTest https://research.rug.nl/en/publications/cbb66b9e-bd67-435c-806f-7f301357232fTest https://pure.rug.nl/ws/files/42112470/journal.pgen.1006659.pdfTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.9B24A0CA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1371/journal.pgen.1006659 |
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