GSNO reductase and β2-adrenergic receptor gene-gene interaction: bronchodilator responsiveness to albuterol
GSNO reductase and β2-adrenergic receptor gene-gene interaction: bronchodilator responsiveness to albuterol
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DOI：
10.1097/fpc.0b013e328337f992
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发表时间：
2010-06-01
影响因子：
2.6
通讯作者：
Burchard, Esteban G.
中科院分区：
文献类型：
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作者：
Choudhry, Shweta;Que, Loretta G.;Burchard, Esteban G.
短效吸入性β 2受体激动剂如沙丁胺醇用于支气管扩张，是全球哮喘治疗的主要药物。支气管扩张剂对沙丁胺醇的反应性不仅在个体之间存在显著差异，而且在人种/种族组之间也存在显著差异。β（2）-肾上腺素能受体（β（2）AR）是β（2）-激动剂药物的靶标。S-亚硝基谷胱甘肽还原酶（GSNOR）调节内源性支气管扩张剂S-亚硝基谷胱甘肽的水平，目的我们假设GSNOR和β（2）AR基因变异体之间存在药物遗传学相互作用，这些基因变异体与沙丁胺醇的可变反应相关。在609个波多黎各和墨西哥哮喘家族中，对GSNOR基因变异与哮喘及相关表型的相关性进行了检测。此外，我们使用线性回归测试了这些个体的GSNOR和β（2）AR基因变异体之间的药物遗传学相互作用以及对沙丁胺醇的反应性。结果在波多黎各人中，几个GSNOR单核苷酸多态性和3 'UTR中的一个单倍型与哮喘风险增加和支气管扩张剂反应性降低显著相关（P = 0.04-0.007）。GSNOR风险单倍型影响GSNOR mRNA和蛋白的表达，表明功能的获得。此外，基因-基因相互作用分析提供了GSNOR和β（2）AR基因变异体之间的药物遗传学相互作用以及波多黎各人（P = 0.03）、墨西哥人（P = 0.15）和波多黎各和墨西哥合并哮喘患者（P = 0.003）对沙丁胺醇的反应的证据。GSNOR+17059* β（2）AR+46基因型组合（TG+GG*AG和TG+GG*GG）与较低的支气管扩张剂反应相关。结论GSNOR和β（2）AR基因分型可能有助于识别拉丁美洲个体，这些个体可能从难治性哮喘的辅助治疗中获益。药理遗传学和基因组学20：351-358（C）2010年沃尔特斯·克鲁沃健康垂直栏Lippincott威廉姆斯&威尔金斯。
Background Short-acting inhaled beta(2)-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The beta(2)-adrenergic receptor (beta(2)AR) is the target for beta(2)-agonist drugs. The enzyme, S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to beta(2)-agonists.Objective We hypothesized that there are pharmacogenetic interactions between GSNOR and beta(2)AR gene variants that are associated with variable response to albuterol.Methods We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these individuals for pharmacogenetic interaction between GSNOR and beta(2)AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants.Results Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3'UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (P = 0.04-0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene-gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and beta(2)AR gene variants and the response to albuterol in Puerto Rican (P = 0.03), Mexican (P = 0.15) and combined Puerto Rican and Mexican asthmatics (P = 0.003). Specifically, GSNOR+17059*beta(2)AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response.Conclusion Genotyping of GSNOR and beta(2)AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma. Pharmacogenetics and Genomics 20: 351-358 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.