Tantisira Kelan G, Hwang Eun Sook, Raby Benjamin A, Silverman Eric S, Lake Stephen L, Richter Brent G, Peng Stanford L, Drazen Jeffrey M, Glimcher Laurie H, Weiss Scott T
Channing Laboratory and Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18099-104. doi: 10.1073/pnas.0408532102. Epub 2004 Dec 16.
TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naive T lymphocyte development and has been implicated in asthma pathogenesis. Specifically, the T-bet knockout mouse spontaneously develops airway hyperresponsiveness and other changes consistent with asthma. Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion. Here we demonstrate that the nonsynonymous variation in TBX21 coding for replacement of histidine 33 with glutamine is associated with significant improvement in the PC(20) (a measure of airway responsiveness) of asthmatic children in a large clinical trial spanning 4 years. We note that this increase occurs only in the children randomized to inhaled corticosteroids and that it dramatically enhances the overall improvement in PC(20) associated with inhaled corticosteroid usage. The average PC(20) at trial end for subjects on inhaled corticosteroids possessing a variant allele was in the normal range for nonasthmatics. In cellular models, we show that the TBX21 variant increases T helper 1 and decreases T helper 2 cytokine expression comparably with wild type. TBX21 may thus be an important determinant pharmacogenetic response to the therapy of asthma with inhaled corticosteroids.
TBX21编码转录因子T-bet（在T细胞中表达的T盒），它影响初始T淋巴细胞的发育，并与哮喘发病机制有关。具体而言，T-bet基因敲除小鼠会自发出现气道高反应性及其他与哮喘相符的变化。由于哮喘患者使用吸入性糖皮质激素可调节气道反应性，因此可以推测TBX21的基因变异可能以治疗特异性方式改变哮喘表型。在此我们证明，在一项为期4年的大型临床试验中，TBX21编码区将组氨酸33替换为谷氨酰胺的非同义变异与哮喘儿童的PC20（气道反应性的一种衡量指标）显著改善相关。我们注意到，这种增加仅发生在随机接受吸入性糖皮质激素治疗的儿童中，并且它显著增强了与吸入性糖皮质激素使用相关的PC20的总体改善。在试验结束时，具有变异等位基因的接受吸入性糖皮质激素治疗的受试者的平均PC20处于非哮喘患者的正常范围内。在细胞模型中，我们表明TBX21变异体与野生型相比，同等程度地增加辅助性T细胞1（Th1）细胞因子表达并降低辅助性T细胞2（Th2）细胞因子表达。因此，TBX21可能是吸入性糖皮质激素治疗哮喘的药物遗传学反应的一个重要决定因素。
