Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.
Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.
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DOI：
10.1016/s0140-6736(09)61492-6
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发表时间：
2009-11-21
期刊：
影响因子：
168.9
通讯作者：
Israel, Elliot
中科院分区：
文献类型：
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作者：
Wechsler, Michael E.;Kunselmon, Susan J.;Chinchilli, Vernon M.;Bleecker, Eugene;Boushey, Homer A.;Calhoun, William J.;Ameredes, Bill T.;Castro, Mario;Craig, Timothy J.;Denlinger, Loren;Fahy, John V.;Jarjour, Nizar;Kazani, Shamsah;Kim, Sophia;Kraft, Monica;Lazarus, Stephen C.;Lemanske, Robert F., Jr.;Markezich, Amy;Martin, Richard J.;Permaul, Perdita;Peters, Stephen P.;Ramsdell, Joe;Sorkness, Christine A.;Sutherland, E. Rand;Szefler, Stanley J.;Walter, Michael J.;Wasserman, Stephen I.;Israel, Elliot
长效β2受体激动剂和吸入性皮质类固醇（LABA/ICS）联合治疗可改善许多哮喘患者的预后。一些研究表明，β2肾上腺素能受体第16位氨基酸精氨酸纯合子（B16 Arg/Arg）患者的获益低于B16 Gly/Gly患者。在一项由NIH资助的、B16基因型分层、前瞻性、随机、双盲、安慰剂对照、交叉试验（www.ClinicalTrials.gov注册ID NCT 00200967）中，我们比较了在中度哮喘患者中在ICS基础上加用沙美特罗或安慰剂，使用AM PEF作为主要结局。18周后，Arg/Arg（n=42）和Gly/Gly（n=45）受试者接受沙美特罗治疗后的AM PEF高于安慰剂组，不同基因型的改善无差异（Arg/Arg 21.4（p<0.0001）vs. Gly/Gly 21.5 L/min（p<0.0001）;基因型间差异为0.1 L/min，95% CI（-14.2，14.4），p=0.99）。在Gly/Gly受试者中，当沙美特罗加入ICS时，乙酰甲胆碱PC 20（次要结果）加倍（p<0.0001），但在Arg/Arg受试者中保持不变（p=0.87）（基因型之间剂量差异加倍1.32（95%CI 0.43，2.21），p=0.0038）。非裔美国人的探索性事后子集分析显示，沙美特罗改善了8名Gly/Gly受试者的AM和PM PEF（分别为29 L/min，p=0.013和45 L/min，p= 0.0005），但未改善9名Arg/Arg受试者的AM和PM PEF（分别为−12 L/min，p=0.57和−2.2 L/min，p=0.92）。B16 Arg/Arg和Gly/Gly患者在沙美特罗加用中等剂量ICS后气道功能改善。虽然这些数据提供了保证，在一般人群中，这些多态性不应改变LABA与中等剂量ICS的使用，但在气道反应性中基因型差异反应的意义有利于Gly/Gly受试者和非裔美国人的事后分析需要进一步研究。
Combined long-acting β2-agonist and inhaled corticosteroid (LABA/ICS) therapy improves outcomes in many asthmatics. Some studies suggest that patients homozygous for arginine at the 16th amino-acid position of the β2 adrenergic receptor (B16 Arg/Arg) benefit less than those with B16 Gly/Gly. In an NIH-funded, B16 genotype-stratified, prospective, randomized, double-blind, placebo-controlled, cross-over trial (www.ClinicalTrials.gov registration ID NCT00200967), we compared adding salmeterol or placebo to ICS in patients with moderate asthma, using AM PEF as the primary outcome. After 18 weeks, Arg/Arg (n=42) and Gly/Gly (n=45) subjects had greater AM PEF with salmeterol than placebo, with no difference in improvement by genotype (Arg/Arg 21.4 (p<0.0001) vs. Gly/Gly 21.5 L/min (p<0.0001); 0.1 L/min difference between genotypes, 95% CI (−14.2, 14.4), p=0.99). In Gly/Gly subjects, methacholine PC20 (a secondary outcome) doubled when salmeterol was added to ICS (p<0.0001), but remained unchanged in Arg/Arg subjects (p=0.87) (1.32 doubling dose difference between genotypes (95%CI 0.43,2.21), p=0.0038). An exploratory posthoc subset analysis of African Americans showed that salmeterol improved the AM and PM PEF for the 8 Gly/Gly subjects (29 L/min, p=0.013 and 45 L/min, p= 0.0005, respectively) but not for the 9 Arg/Arg subjects (−12 L/min, p=0.57 and−2.2 L/min, p=0.92, respectively). B16 Arg/Arg and Gly/Gly patients experience improved airway function with salmeterol added to moderate-dose ICS. While these data provide reassurance that in the general population these polymorphisms should not alter the use of LABA with moderate-dose ICS, the significance of the genotype-differentiated response in airway reactivity favoring Gly/Gly subjects and the post-hoc analysis in African Americans require further investigation.