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

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. © 2017 smith et al.