GSNO 还原酶和β2-肾上腺素能受体基因-基因相互作用：对沙丁胺醇的支气管扩张剂反应性。
GSNO reductase and beta2-adrenergic receptor gene-gene interaction: bronchodilator responsiveness to albuterol.
机构信息
Lung Biology Center, University of California, San Francisco, California 94143-2911, USA.
出版信息
Pharmacogenet Genomics. 2010 Jun;20(6):351-8. doi: 10.1097/FPC.0b013e328337f992.
BACKGROUND
Short-acting inhaled beta2-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 beta2-adrenergic receptor (beta2AR) is the target for beta2-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 beta2-agonists.
OBJECTIVE
We hypothesized that there are pharmacogenetic interactions between GSNOR and beta2AR 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 beta2AR 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 beta2AR 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+17059beta2AR+46 genotype combinations (TG+GGAG and TG+GG*GG) were associated with lower bronchodilator response.
CONCLUSION
Genotyping of GSNOR and beta2AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma.
背景
短效吸入型β2 受体激动剂如沙丁胺醇，用于支气管扩张，是全球哮喘治疗的基石。不仅个体之间，而且不同种族/族群之间，对沙丁胺醇的支气管扩张反应存在显著差异。β2 肾上腺素能受体（β2AR）是β2 激动剂药物的靶标。调节内源性支气管扩张剂 S-亚硝基谷胱甘肽水平的酶 S-亚硝基谷胱甘肽还原酶（GSNOR）已被证明可调节对β2 激动剂的反应。
目的
我们假设 GSNOR 和β2AR 基因变异之间存在药物遗传学相互作用，这些相互作用与对沙丁胺醇的可变反应有关。
方法
我们对 609 个有哮喘的波多黎各和墨西哥家族进行了基于家庭的分析，以测试 GSNOR 基因变异与哮喘和相关表型之间的关联。此外，我们使用线性回归测试了 GSNOR 和β2AR 基因变异与沙丁胺醇反应之间的药物遗传学相互作用。细胞转染实验用于测试 GSNOR 基因变异的潜在影响。
结果
在波多黎各人中，3'UTR 中的几个 GSNOR SNPs 和单倍型与哮喘风险增加和支气管扩张反应降低显著相关（P=0.04-0.007）。GSNOR 风险单倍型影响 GSNOR mRNA 和蛋白的表达，表明获得功能。此外，基因-基因相互作用分析提供了证据表明，GSNOR 和β2AR 基因变异与波多黎各人（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）对沙丁胺醇的反应之间存在药物遗传学相互作用。具体而言，GSNOR+17059β2AR+46 基因型组合（TG+GGAG 和 TG+GG*GG）与较低的支气管扩张反应相关。
结论
GSNOR 和β2AR 基因的基因分型可能有助于识别可能受益于难治性哮喘辅助治疗的拉丁裔个体。
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