Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma
Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma
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DOI：
10.1165/rcmb.2009-0418oc
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发表时间：
2011-06-01
影响因子：
6.4
通讯作者：
Tamari, Mayumi
中科院分区：
文献类型：
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作者：
Harada, Michishige;Hirota, Tomomitsu;Tamari, Mayumi
胸腺基质淋巴生成素（TSLP）触发树突状细胞介导的辅助性T (Th) 2炎症反应。TSLP基因启动子区域的单核苷酸多态性（SNP） rs3806933为转录因子激活蛋白(AP)-1创造了一个结合位点。该变异增强了AP-1与调节元件的结合，并增加了TSLP对正常人支气管上皮（NHBE）中多肌苷-多胞酸（poly[I:C]）刺激的启动子报告活性。我们研究了包括SNP rs3806933在内的多态性是否会影响支气管哮喘的易感性和临床表型。我们选择了三个具有代表性的snp（即Tag），使用两个独立的人群（分别为639例儿童特应性哮喘患者和838例对照，以及641例成人哮喘患者和376例对照）对TSLP基因进行关联研究。我们进一步研究了皮质类固醇和长效β(2)受体激动剂（沙美特罗）对NHBE中poly（I: C）的TSLP基因表达水平的影响。我们发现启动子多态性rs3806933和rs2289276与儿童特应性哮喘和成人哮喘的疾病易感性显著相关。功能SNP rs3806933与哮喘相关（meta分析，P = 0.000056；优势比为1.29；95%可信区间为1.14-1.47）。rs2289278基因型与肺功能相关。此外，poly（I: C）在NHBE中诱导的TSLP mRNA和蛋白表达被皮质类固醇和沙美特罗协同破坏。TSLP变异与支气管哮喘和肺功能显著相关。因此，TSLP可作为联合治疗的靶分子。
Thymic stromal lymphopoietin(TSLP) triggers dendritic cell-mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter-reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting beta(2)-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I: C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I: C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.