Format

Send to

Choose Destination
PLoS Genet. 2017 Mar 8;13(3):e1006659. doi: 10.1371/journal.pgen.1006659. eCollection 2017 Mar.

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

Author information

1
Amgen Inc., Discovery Research, South San Francisco, California, United States of America.
2
deCODE genetics / Amgen Inc., Reykjavík, Iceland.
3
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
4
Department of Medicine, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
5
The Laboratory in Mjodd, RAM, Reykjavik, Iceland.
6
Department of Clinical Biochemistry, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
7
Laboratory Hematology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
8
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
9
Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
10
Department of Respiratory Medicine and Sleep, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
11
Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
12
GRIAC research institute, Groningen, The Netherlands.
13
University Medical Center Groningen, University of Groningen, Department of Epidemiology, Groningen, The Netherlands.
14
Center for Pediatrics, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
15
Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen University, Copenhagen, Denmark.
16
COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
17
University Medical Center Groningen, University of Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands.

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.

PMID:
28273074
PMCID:
PMC5362243
DOI:
10.1371/journal.pgen.1006659
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center