A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma
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A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. / 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; Bønnelykke, Klaus; Bisgaard, Hans; Masson, Gisli; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F; Johnston, James A; Jonsdottir, Ingileif; Stefansson, Kari.
In: P L o S Genetics, Vol. 13, No. 3, e1006659, 2017.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma
AU - Smith, Dirk
AU - Helgason, Hannes
AU - Sulem, Patrick
AU - Bjornsdottir, Unnur Steina
AU - Lim, Ai Ching
AU - Sveinbjornsson, Gardar
AU - Hasegawa, Haruki
AU - Brown, Michael
AU - Ketchem, Randal R
AU - Gavala, Monica
AU - Garrett, Logan
AU - Jonasdottir, Adalbjorg
AU - Jonasdottir, Aslaug
AU - Sigurdsson, Asgeir
AU - Magnusson, Olafur T
AU - Eyjolfsson, Gudmundur I
AU - Olafsson, Isleifur
AU - Onundarson, Pall Torfi
AU - Sigurdardottir, Olof
AU - Gislason, David
AU - Gislason, Thorarinn
AU - Ludviksson, Bjorn Runar
AU - Ludviksdottir, Dora
AU - Boezen, H Marike
AU - Heinzmann, Andrea
AU - Krueger, Marcus
AU - Porsbjerg, Celeste
AU - Ahluwalia, Tarunveer S
AU - Waage, Johannes
AU - Backer, Vibeke
AU - Deichmann, Klaus A
AU - Koppelman, Gerard H
AU - Bønnelykke, Klaus
AU - Bisgaard, Hans
AU - Masson, Gisli
AU - Thorsteinsdottir, Unnur
AU - Gudbjartsson, Daniel F
AU - Johnston, James A
AU - Jonsdottir, Ingileif
AU - Stefansson, Kari
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Alternative Splicing
KW - Animals
KW - Asthma/genetics
KW - Binding Sites
KW - Biological Assay
KW - Child
KW - Child, Preschool
KW - Denmark
KW - Eosinophils/metabolism
KW - Female
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Heterozygote
KW - Humans
KW - Iceland
KW - Infant
KW - Infant, Newborn
KW - Interleukin-33/genetics
KW - Introns
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Middle Aged
KW - Mutation
KW - Netherlands
KW - Young Adult
U2 - 10.1371/journal.pgen.1006659
DO - 10.1371/journal.pgen.1006659
M3 - Journal article
C2 - 28273074
VL - 13
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 3
M1 - e1006659
ER -
ID: 194772161