A rare missense variant in STAT6 that protects against asthma

Scientists at deCODE genetics, a subsidiary of Amgen, and collaborators have published a study in Journal of Allergy and Clinical Immunology reporting a rare missense variant in STAT6 that protects against asthma.

Asthma is a complex and heterogenous chronic inflammatory disease of the airways which affects an estimated 300 million people worldwide. It is estimated that up to 5-10% of asthma patients have severe steroid-resistant asthma. The missense variant described in this paper leads to reduced levels of the STAT6 protein in activated T-cells and weaker T2 mediated response from several downstream genes. It therefore, reduces the capability of cells to respond to and further activate T2 inflammatory response.

The variant protects against asthma, most significantly against moderately severe to severe T2 high asthma, with carriers of the variant being 73% less likely to develop such disease than non-carriers.  Reduction of other T2 molecules and cell types were also observed to significantly associate with the variant, including IgE, eosinophils and basophils.

The missense variant is vanishingly rare outside Iceland that excludes direct replication of this particular association in other cohorts. However, similar effect was detected for asthma and eosinophil count in Iceland, Denmark and UK when running a burden test, combining all rare variants with predicted loss of function or deleterious effects in STAT6.

The pathway to which STAT6 belongs is highly targeted by asthma biologics, with each drug targeting a single molecule within the T2 inflammatory response. Downregulating STAT6 in a clinical setting may, therefore, combine the effects of many of these drugs, making it an attractive target for drug development to treat severe, uncontrolled T2 high asthma.