Impact of the Arg 16 Allele of the B2AR Gene on the Effect of Withdrawal of LABA in Patients with Moderate to Severe Asthma

Introduction: Long acting beta agonists (LABAs) are effective for controlling asthma, however questions about their safety have led to concerns over use. Genetic polymorphisms at the 16 amino acid position of the beta-2 adrenergic receptor gene (B2AR) may be associated with increased risk. Methods: A randomized, double blind study was conducted in patients with moderate to severe asthma being treated with combined inhaled corticosteroids/LABA (ICS/LABA), comparing the effect of LABA continuation versus withdrawal on asthma outcomes among patients stratified by B2AR genotype (Arg/Arg vs. Gly/Gly at the 16^th amino acid position). Results: 67 participants (31 Arg/Arg, 36 Gly/Gly) were randomized to receive fluticasone alone (F) or continue combined fluticasone/salmeterol (F/S) after a run-in period on F/S. Among Gly/Gly subjects, those in the F/S treatment group showed improvement in AM PEFR (+ 8.4 L/s) whereas those receiving F alone experienced a reduction in AM PEFR over the study period (−14.4 L/s), (p = 0.06). There was no significant difference in morning peak expiratory flow rate (AM PEFR) in Arg/Arg participants randomized to receive F/S (−15.7L) vs F alone (−5.6 L/s) (p = 0.61). There was no significant difference in exacerbations in the Arg/Arg subjects treated with F/S compared with those treated with F (p = 0.65). Conclusions: Withdrawal of LABA therapy in asthmatics with the Arg/Arg genotype at the 16^th amino acid position of B2AR did not lead to significant improvement in AM PEFR. LABA withdrawal in the Gly/Gly genotype however led to a borderline significant decline in AM PEFR.

引言：长效β₂受体激动剂（Long acting beta agonists, LABA）可有效控制哮喘，但针对其安全性的质疑引发了临床应用担忧。β₂肾上腺素能受体基因（beta-2 adrenergic receptor gene, B2AR）第16位氨基酸位点的基因多态性，可能与哮喘不良风险升高相关。
方法：本研究开展一项随机双盲试验，纳入接受吸入性糖皮质激素/LABA联合治疗（inhaled corticosteroids/LABA, ICS/LABA）的中重度哮喘患者，按B2AR基因型（第16位氨基酸为Arg/Arg与Gly/Gly）进行分层，比较持续使用LABA与停用LABA对哮喘转归的影响。
结果：共67名受试者（31名Arg/Arg型，36名Gly/Gly型）在接受F/S导入期后，被随机分配至单用氟替卡松（F）组或继续联合氟替卡松/沙美特罗（F/S）组。在Gly/Gly型受试者中，接受F/S治疗者的晨间峰流速（morning peak expiratory flow rate, AM PEFR）较基线升高8.4 L/s，而单用F组受试者的晨间峰流速在研究期间下降14.4 L/s（p=0.06）。在Arg/Arg型受试者中，随机至F/S组者的晨间峰流速变化为-15.7 L/s，单用F组为-5.6 L/s，组间无显著差异（p=0.61）。Arg/Arg型受试者的哮喘急性加重发生率在F/S组与F组间亦无显著差异（p=0.65）。
结论：对于B2AR基因第16位氨基酸为Arg/Arg基因型的哮喘患者，停用LABA治疗并未使晨间峰流速出现显著改善。而在Gly/Gly基因型患者中，停用LABA则导致晨间峰流速出现临界显著的下降。