Forskning ved Københavns Universitet - Københavns Universitet


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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt


  • 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
  • Tarunveer S Ahluwalia
  • Johannes Waage
  • Klaus A Deichmann
  • Gerard H Koppelman
  • Gisli Masson
  • Unnur Thorsteinsdottir
  • Daniel F Gudbjartsson
  • James A Johnston
  • Ingileif Jonsdottir
  • Kari Stefansson

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.

TidsskriftP L o S Genetics
Udgave nummer3
Antal sider24
StatusUdgivet - 2017

Antal downloads er baseret på statistik fra Google Scholar og

Ingen data tilgængelig

ID: 194772161