학술논문
A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.
Document Type
article
Author
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
Source
PLoS Genetics, Vol 13, Iss 3, p e1006659 (2017)
Subject
Language
English
ISSN
1553-7390
1553-7404
1553-7404
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.