Photo Credit: JUAN GAERTNER

The following is a summary of “A partial loss-of-function variant in STAT6 protects against T2 asthma,” published in the October 2024 issue of Allergy and Immunology by Kristjansdottir et al. 

Signal Transducer and Activator of Transcription 6 (STAT6) is vital in Type 2 (T2) inflammation, with common non-coding variants at the STAT6 locus linked to T2 inflammatory conditions, including asthma, often targeted in treatment to enhance patient outcomes. 

Researchers conducted a retrospective study to investigate the association of the rare missense variant p.L406P in STAT6 with T2 inflammatory traits, including asthma and allergic diseases. 

They examined the association of the p.L406P variant with plasma protein levels, white blood cell counts, and the risk of asthma and allergic phenotypes, using a burden test for validation in other cohorts. The impact of p.L406P on STAT6 function was analyzed in cell lines and by comparing CD4⁺ T-cell responses of carriers and non-carriers. 

The results showed that p.L406P was associated with reduced plasma levels of STAT6 and immunoglobulin E (IgE), along with lower eosinophil and basophil counts. It also provided protection against severe T2 asthma and demonstrated that p.L406P led to lower interleukin-4 (IL-₄)-induced activation in luciferase reporter assays and decreased STAT6 levels in CD4⁺ T cells. Additionally, they identified multiple genes with expression altered by the p.L406P genotype after IL-₄ treatment, indicating a weaker IL-₄ response in carriers compared to non-carriers. 

The study concluded that a partial loss-of-function variant in STAT6 reduces IL-₄ responses and protects against T2 high asthma, indicating STAT6 as a potential therapeutic target. 

Source: jacionline.org/article/S0091-6749(24)01029-7/fulltext