Tantisira Kelan G, Small Kersten M, Litonjua Augusto A, Weiss Scott T, Liggett Stephen B
Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Hum Mol Genet. 2005 Jun 15;14(12):1671-7. doi: 10.1093/hmg/ddi175. Epub 2005 May 6.
In asthma, the response to beta-agonists acting at beta2-adrenergic receptors (beta2AR) displays extensive interindividual variation. One effector for airway beta2AR, adenylyl cyclase type 9 (AC9), was considered a candidate locus for predicting beta-agonist efficacy in the absence and presence of corticosteroid treatment. One non-synonymous AC9 polymorphism has been identified, which results in substitution of Met for Ile at amino acid 772. Under standard culture conditions in stably transfected cells, we found decreased catalytic activity of Met772. However, cells cultured in the presence of glucocorticoid expressing Met772 had a significantly increased albuterol-stimulated adenylyl cyclase response (approximately 80%) when compared with those expressing Ile772 (approximately 20%, P=0.02). An equivalent increase in beta2AR expression was observed in both lines due to glucocorticoid, but AC9 expression was unaffected. The hypothesis that Met772-AC9 is associated with an improved albuterol bronchodilator response in asthmatics was investigated in 436 asthmatic children who were followed for 4 years and randomized to receive placebo or the inhaled corticosteroid budesonide. Met772 carriers on budesonide showed a significant improvement in forced expiratory volume in 1 s (P=0.005). Moreover, a highly significant interaction (P=0.002) was found for budesonide treatment and the AC9 polymorphism. These in vitro and human association studies are consistent with this AC9 polymorphism altering albuterol responsiveness in the context of concomitant inhaled corticosteroid administration, which is a common asthma regimen. The Met772-AC9 polymorphism represents one of most likely several multi-gene polymorphisms along the receptor-relaxation axis, which together may provide for a composite pharmacogenetic index for asthma therapy.
在哮喘中，对作用于β2肾上腺素能受体（β2AR）的β激动剂的反应存在广泛的个体间差异。气道β2AR的一种效应器，即9型腺苷酸环化酶（AC9），被认为是在无糖皮质激素治疗和有糖皮质激素治疗的情况下预测β激动剂疗效的候选基因座。已鉴定出一种非同义AC9多态性，其导致第772位氨基酸处的甲硫氨酸（Met）替代异亮氨酸（Ile）。在稳定转染细胞的标准培养条件下，我们发现Met772的催化活性降低。然而，与表达Ile772的细胞（约20%，P = 0.02）相比，在表达Met772的糖皮质激素存在下培养的细胞，沙丁胺醇刺激的腺苷酸环化酶反应显著增加（约80%）。由于糖皮质激素，在两条细胞系中均观察到β2AR表达等量增加，但AC9表达未受影响。在436名哮喘儿童中进行了研究，这些儿童随访4年并随机接受安慰剂或吸入性糖皮质激素布地奈德，以探讨Met772 - AC9与哮喘患者沙丁胺醇支气管扩张反应改善相关的假说。接受布地奈德治疗的Met772携带者的1秒用力呼气量有显著改善（P = 0.005）。此外，发现布地奈德治疗与AC9多态性之间存在高度显著的相互作用（P = 0.002）。这些体外和人体关联研究表明，这种AC9多态性在同时吸入糖皮质激素的情况下会改变沙丁胺醇的反应性，而吸入糖皮质激素是常见的哮喘治疗方案。Met772 - AC9多态性代表了沿受体 - 舒张轴最有可能的几种多基因多态性之一，它们共同可能为哮喘治疗提供一个复合药物遗传学指标。
