The Mutation Preventing Asthma

Inhaler / Stuart B

Research from deCODE Genetics has identified a rare loss-of-function mutation that protects the carrier from asthma and reduces their blood eosinophil count. The study, published in PLOS Genetics, has shown that a mutation within the IL-33 gene disrupts the synthesis of the corresponding protein, which significantly lowers the risk of asthma developing. This new understanding of the gene and the protein may provide a novel drug target for the treatment of asthma and allergic diseases.

IL-33 is a tissue-derived cytokine known to be associated with the induction and amplification of inflammation in eosinophils, a type of white blood cell. The immune system uses eosinophils in a number of ways, including within the inflammation of the airways during an asthma attack. Previous work by the same team has identified common variants within the IL-33 gene and the IL1RL1 gene, which encodes for the IL-33 receptor ST2, that correspond to changes in eosinophil counts and occurrences of asthma.

“Based on this knowledge, we decided to use high resolution sequencing technology to search for variants in these genes that cause changes in structure and function of the proteins they encode,” the authors wrote.


deCODE Genetics founder, Dr. Stefánsson raised $12 million in six weeks and founded the company that would allow him to take the field of human genetics forward into a new era


Using whole genome sequencing within the Icelandic population (8,453 participants), the team were able to identify a novel mutation within the IL-33 gene that knocked out gene function. The variant disrupted a canonical splice acceptor site before the last coding exon, resulting in a premature stop codon that truncated the IL-33 protein at 66 amino acids long. While the mutated protein displayed normal intracellular localisation, it was unable to bind with the ST2 receptor or to activate ST2-expressing cells, thereby inhibiting its function. In theory, without functional IL-33, eosinophil amplification cannot be triggered and no asthma response will be seen.

The team were also able to demonstrate that in cases where one functional allele and one mutated allele, the IL-33 gene was insufficiently expressed to trigger an asthma attack.

Our understanding of the genetic factors behind asthma is still very limited and despite the rarity of the mutation, this research is a good step towards building a picture of the mechanisms involved in the condition. The IL-33 and IL1RL1 genes now also provide a potential route for future drug treatments.

“This rare mutation causes reduced number of eosinophils in blood and protects against asthma,” the authors wrote. “These results suggest that drugs that could interfere with the inflammatory activity of the IL33 protein may be beneficial for treatment of asthma.”