
Researchers at deCODE genetics, a biopharmaceutical company in Reykjavík, Iceland, have identified a rare variant in the STAT6 gene that offers protection against severe type 2 (T2) asthma. STAT6 is crucial for inflammation and is involved in asthma and allergic diseases.
The variant, p.L406P, reveals significant implications for asthma treatment and the potential for new therapeutic targets. Common noncoding variants in STAT6 are linked to type 2 asthma inflammatory traits and are targeted in asthma treatments. The study, “A Partial Loss-of-Function Variant in STAT6 Protects Against Type 2 Asthma,” was published in the Journal of Allergy and Clinical Immunology.
The study involved genetic analysis and functional experiments with plasma protein levels, white blood cell counts and the risk of asthma and allergic phenotypes. Researchers tested the association of the p.L406P variant with various inflammatory traits and asthma risk using data from Icelandic cohorts. They examined functional consequences through cell culture assays and CD4+ T-cell response analysis.
From the research, the study’s authors discovered:
- The p.L406P variant in the STAT6 gene is associated with reduced plasma levels of STAT6 and immunoglobulin E (IgE) as well as lower eosinophil and basophil counts in the blood. This variant provides protection against severe type 2 asthma.
- The variant leads to a partial loss of function in STAT6, resulting in dampened IL-4 responses. This effect was observed in both cell culture experiments and in CD4+ T cells from carriers of the variant.
- Individuals carrying the p.L406P variant showed a significantly lower risk of developing severe type 2 asthma, with the odds ratio (OR) for asthma risk being 0.75. The protective effect was most pronounced in patients with high eosinophil counts.
- The variant is rare outside of Iceland, limiting the ability to detect associations in other populations.
According to researchers, the findings suggest that targeting STAT6 could be a promising strategy for treating severe, uncontrolled type 2 asthma. Current asthma biologics target various points in the IL-4/IL-13 signaling pathway, but downregulating STAT6 might combine the effects of multiple drugs, offering a more comprehensive treatment approach.