Impact of the Arg 16 allele of the B2AR gene on the effect of withdrawal of LABA in patients with moderate to severe asthma

<i>Introduction</i>: 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. <i>Methods</i>: 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 16th amino acid position). <i>Results</i>: 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), (<i>p</i> = 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) (<i>p</i> = 0.61). There was no significant difference in exacerbations in the Arg/Arg subjects treated with F/S compared with those treated with F (<i>p</i> = 0.65). <i>Conclusions</i>: Withdrawal of LABA therapy in asthmatics with the Arg/Arg genotype at the 16th 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, LABAs）是哮喘控制的有效用药，但围绕其安全性的争议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，可能与哮喘患者使用LABA的风险升高相关。【方法】本研究针对接受吸入性糖皮质激素/长效β₂受体激动剂联合治疗（inhaled corticosteroids/LABA, ICS/LABA）的中重度哮喘患者，开展一项随机双盲试验。研究按B2AR基因型（第16位氨基酸为Arg/Arg vs 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】本研究共纳入67名受试者，其中31名为Arg/Arg基因型，36名为Gly/Gly基因型。所有受试者在接受氟替卡松/沙美特罗（F/S）导入期治疗后，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）治疗组。在Gly/Gly基因型受试者中，接受F/S治疗者的晨间峰流速（morning peak expiratory flow rate, AM PEFR）较基线提升8.4 L/s，而单用F治疗者的AM PEFR在研究期间下降14.4 L/s（p=0.06）。在Arg/Arg基因型受试者中，随机分配至F/S组者的AM PEFR变化为-15.7 L/s，单用F组为-5.6 L/s，组间差异无统计学意义（p=0.61）。Arg/Arg基因型受试者中，F/S治疗组与F治疗组的哮喘急性加重发生率无显著差异（p=0.65）。【结论】对于B2AR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AM PEFR出现显著改善。而对于Gly/Gly基因型患者，停用LABA则会导致AM PEFR出现临界显著的下降。