STAT6 中的部分功能丧失变异可预防2型哮喘
2025/03/03
摘要
背景：信号转导及转录激活因子6（STAT6）在2型（T2）炎症反应中起核心作用，STAT6基因位点的常见非编码变异与多种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：我们旨在测试STAT6中的一个罕见错义变异p.L406P与T2炎症特征的关联，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：测试了p.L406P与血浆蛋白水平、白细胞计数以及哮喘和过敏表型风险的关联。还使用负担检验测试了其他队列中的显著关联。通过细胞系和比较携带者和非携带者CD4(+) T细胞反应，检测了p.L406P对STAT6蛋白功能的影响。
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有关。它还可以预防哮喘，主要是严重的高T2型哮喘。p.L406P导致荧光素酶报告基因测定中IL-4诱导的活化降低，CD4（+）T细胞中STAT6水平降低。我们鉴定了多个基因，其表达受IL-4处理CD4（+）T细胞时p.L406P基因型的影响；这种效应与携带者中较弱的IL-4反应一致，而非携带者中则较强。
结论：STAT6的部分功能丧失变异导致IL-4反应减弱和对高T2型哮喘的保护，表明STAT6是一种有吸引力的治疗靶点。
背景：信号转导及转录激活因子6（STAT6）在2型（T2）炎症反应中起核心作用，STAT6基因位点的常见非编码变异与多种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：我们旨在测试STAT6中的一个罕见错义变异p.L406P与T2炎症特征的关联，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：测试了p.L406P与血浆蛋白水平、白细胞计数以及哮喘和过敏表型风险的关联。还使用负担检验测试了其他队列中的显著关联。通过细胞系和比较携带者和非携带者CD4(+) T细胞反应，检测了p.L406P对STAT6蛋白功能的影响。
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有关。它还可以预防哮喘，主要是严重的高T2型哮喘。p.L406P导致荧光素酶报告基因测定中IL-4诱导的活化降低，CD4（+）T细胞中STAT6水平降低。我们鉴定了多个基因，其表达受IL-4处理CD4（+）T细胞时p.L406P基因型的影响；这种效应与携带者中较弱的IL-4反应一致，而非携带者中则较强。
结论：STAT6的部分功能丧失变异导致IL-4反应减弱和对高T2型哮喘的保护，表明STAT6是一种有吸引力的治疗靶点。
（中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校）
（J Allergy Clin Immunol 2025 Jan;155(1):228-235;DOI: 10.1016/j.jaci.2024.10.002.IF: 10.228）
A partial loss-of-function variant in STAT6 protects against type 2 asthma.
Katla, Kristjansdottir; Gudmundur L,
Abstrast
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.
Katla, Kristjansdottir; Gudmundur L,
Abstrast
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.
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