Tachdjian et al. establish that an allergy-associated gene variant common in African Americans promotes airway inflammation in mice, pointing the way to possible new approaches for asthma treatment.

Genetic association studies link the Q576R polymorphism in the gene encoding the interleukin (IL)-4 receptor with susceptibility to severe asthma. This receptor responds to the pro-allergy cytokines IL-4 and IL-13, and the polymorphism swaps one amino acid in its alpha chain. Like asthma, this genetic variant is prevalent in African Americans, about half of whom are homozygous for the polymorphism. Because genetic associations don't confirm a cause-and-effect relationship, Tachdjian et al. set out to verify the pro-asthma effect of the Q576R polymorphism by expressing the mutation in mice.

Mice carrying the Q576R polymorphism developed extreme airway inflammation, similar to that shown by asthma patients. Inflammation-promoting eosinophils swept in, mucus-exuding goblet cells multiplied, and the airways stiffened as collagen built up.

IL-4 and IL-13 typically work by firing up the transcription factor STAT6. However, the polymorphism didn't alter STAT6 activity. Rather, it amplified some of the responses spurred by STAT6, suggesting activation of an alternative pathway that synergizes with STAT6. In fact, activation of the MAP kinase pathway was ramped up in mice with the Q576R allele.