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

Dirk Smith; Hannes Helgason; Patrick Sulem; Unnur Steina Bjornsdottir; Ai Ching Lim; Gardar Sveinbjornsson; Haruki Hasegawa; Michael Brown; Randal R Ketchem; Monica Gavala; Logan Garrett; Adalbjorg Jonasdottir; Aslaug Jonasdottir; Asgeir Sigurdsson; Olafur T Magnusson; Gudmundur I Eyjolfsson; Isleifur Olafsson; Pall Torfi Onundarson; Olof Sigurdardottir; David Gislason; Thorarinn Gislason; Bjorn Runar Ludviksson; Dora Ludviksdottir; H Marike Boezen; Andrea Heinzmann; Marcus Krueger; Celeste Porsbjerg; Tarunveer S Ahluwalia; Johannes Waage; Vibeke Backer; Klaus A Deichmann; Gerard H Koppelman; Klaus Bønnelykke; Hans Bisgaard; Gisli Masson; Unnur Thorsteinsdottir; Daniel F Gudbjartsson; James A Johnston; Ingileif Jonsdottir; Kari Stefansson

doi:10.1371/journal.pgen.1006659

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

Dirk Smith, Hannes Helgason, Patrick Sulem, Unnur Steina Bjornsdottir, Ai Ching Lim, Gardar Sveinbjornsson, Haruki Hasegawa, Michael Brown, Randal R Ketchem, Monica Gavala, Logan Garrett, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Olafur T Magnusson, Gudmundur I Eyjolfsson, Isleifur Olafsson, Pall Torfi Onundarson, Olof Sigurdardottir, David GislasonThorarinn Gislason, Bjorn Runar Ludviksson, Dora Ludviksdottir, H Marike Boezen, Andrea Heinzmann, Marcus Krueger, Celeste Porsbjerg, Tarunveer S Ahluwalia, Johannes Waage, Vibeke Backer, Klaus A Deichmann, Gerard H Koppelman, Klaus Bønnelykke, Hans Bisgaard, Gisli Masson, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, James A Johnston, Ingileif Jonsdottir, Kari Stefansson

Department of Clinical Medicine

51 Citations (Scopus)

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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.

Original language	English
Article number	e1006659
Journal	P L o S Genetics
Volume	13
Issue number	3
Number of pages	24
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1006659
Publication status	Published - Mar 2017

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Alternative Splicing
Animals
Asthma/genetics
Binding Sites
Biological Assay
Child
Child, Preschool
Denmark
Eosinophils/metabolism
Female
Gene Frequency
Genetic Predisposition to Disease
Genotype
Heterozygote
Humans
Iceland
Infant
Infant, Newborn
Interleukin-33/genetics
Introns
Male
Mice
Mice, Transgenic
Middle Aged
Mutation
Netherlands
Young Adult

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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., ... Stefansson, K. (2017). A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. P L o S Genetics, 13(3), [e1006659]. https://doi.org/10.1371/journal.pgen.1006659

Smith, D, Helgason, H, Sulem, P, Bjornsdottir, US, Lim, AC, Sveinbjornsson, G, Hasegawa, H, Brown, M, Ketchem, RR, Gavala, M, Garrett, L, Jonasdottir, A, Jonasdottir, A, Sigurdsson, A, Magnusson, OT, Eyjolfsson, GI, Olafsson, I, Onundarson, PT, Sigurdardottir, O, Gislason, D, Gislason, T, Ludviksson, BR, Ludviksdottir, D, Boezen, HM, Heinzmann, A, Krueger, M, Porsbjerg, C, Ahluwalia, TS, Waage, J, Backer, V, Deichmann, KA, Koppelman, GH, Bønnelykke, K, Bisgaard, H, Masson, G, Thorsteinsdottir, U, Gudbjartsson, DF, Johnston, JA, Jonsdottir, I & Stefansson, K 2017, 'A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma', P L o S Genetics, vol. 13, no. 3, e1006659. https://doi.org/10.1371/journal.pgen.1006659

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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.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Alternative Splicing, Animals, Asthma/genetics, Binding Sites, Biological Assay, Child, Child, Preschool, Denmark, Eosinophils/metabolism, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Iceland, Infant, Infant, Newborn, Interleukin-33/genetics, Introns, Male, Mice, Mice, Transgenic, Middle Aged, Mutation, Netherlands, Young Adult",

author = "Dirk Smith and Hannes Helgason and Patrick Sulem and Bjornsdottir, {Unnur Steina} and Lim, {Ai Ching} and Gardar Sveinbjornsson and Haruki Hasegawa and Michael Brown and Ketchem, {Randal R} and Monica Gavala and Logan Garrett and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Asgeir Sigurdsson and Magnusson, {Olafur T} and Eyjolfsson, {Gudmundur I} and Isleifur Olafsson and Onundarson, {Pall Torfi} and Olof Sigurdardottir and David Gislason and Thorarinn Gislason and Ludviksson, {Bjorn Runar} and Dora Ludviksdottir and Boezen, {H Marike} and Andrea Heinzmann and Marcus Krueger and Celeste Porsbjerg and Ahluwalia, {Tarunveer S} and Johannes Waage and Vibeke Backer and Deichmann, {Klaus A} and Koppelman, {Gerard H} and Klaus B{\o}nnelykke and Hans Bisgaard and Gisli Masson and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F} and Johnston, {James A} and Ingileif Jonsdottir and Kari Stefansson",

year = "2017",

month = mar,

doi = "10.1371/journal.pgen.1006659",

language = "English",

volume = "13",

journal = "P L o S Genetics",

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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 - 2017/3

Y1 - 2017/3

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

SN - 1553-7390

VL - 13

JO - P L o S Genetics

JF - P L o S Genetics

IS - 3

M1 - e1006659

ER -

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

Abstract

Keywords

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