BACKGROUND 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. OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

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STAT6 中的部分功能丧失变异可预防 2 型哮喘。


背景 信号转导和转录激活因子 6 （STAT6） 是 2 型 （T2） 炎症的核心，STAT6 位点的常见非编码变异与各种 T2 炎症特征（包括疾病）相关，其通路在哮喘治疗中被广泛靶向。目的 我们试图测试 STAT6 中一种罕见的错义变异 p.L406P 与 T2 炎症性状的关联，包括哮喘和过敏性疾病的风险，并表征其在细胞培养中的功能后果。方法 检测 p.L406P 与血浆蛋白水平、白细胞计数、哮喘和过敏表型风险的相关性。还使用负担检验测试了其他队列中的显着关联。在细胞系中检测 p.L406P 对 STAT6 蛋白功能的影响，并通过比较来自该变体的携带者和非携带者的 CD4 + T 细胞反应。结果 p.L406P 与血浆 STAT6 和 IgE 水平降低以及血液中嗜酸性粒细胞和嗜碱性粒细胞计数降低相关。它还可以预防哮喘，主要由严重的 T2 高哮喘驱动。p.L406P 导致荧光素酶报告基因测定中 IL-4 诱导的激活降低，CD4+ T 细胞中 STAT6 水平降低。我们鉴定了多个表达受 IL-4 处理 CD4+ T 细胞 p.L406P 基因型影响的基因;该效果与携带者中 IL-4 反应弱于 p.L406P 的非携带者一致。结论 STAT6 中的部分功能丧失变异导致 IL-4 反应减弱并保护免受 T2 高哮喘的影响，表明 STAT6 是一个有吸引力的治疗靶点。