A partial loss-of-function variant in STAT6 protects against type 2 asthma

Signal transducer and activator of transcription 6 (STAT6) is central to type 2 (T2) inflammation, and common noncoding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment. We sought to test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture. The association of p.L406P with plasma protein levels, white blood cell counts, and the risk of asthma and allergic phenotypes was tested. Significant associations in other cohorts were also tested using a burden test. The effects of p.L406P on STAT6 protein function were examined in cell lines and by comparing CD4+ T-cell responses from carriers and noncarriers of the variant. p.L406P associated with reduced plasma levels of STAT6 and IgE as well as with lower eosinophil and basophil counts in blood. It also protected against asthma, mostly driven by severe T2-high asthma. p.L406P led to lower IL-4–induced activation in luciferase reporter assays and lower levels of STAT6 in CD4+ T cells. We identified multiple genes with expression that was affected by the p.L406P genotype on IL-4 treatment of CD4+ T cells; the effect was consistent with a weaker IL-4 response in carriers than in noncarriers of p.L406P. A partial loss-of-function variant in STAT6 resulted in dampened IL-4 responses and protection from T2-high asthma, implicating STAT6 as an attractive therapeutic target.