Bleecker Eugene R, Postma Dirkje S, Lawrance Rachael M, Meyers Deborah A, Ambrose Helen J, Goldman Mitch
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Lancet. 2007 Dec 22;370(9605):2118-25. doi: 10.1016/S0140-6736(07)61906-0.
New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the beta2-adrenergic receptor (ADRB2) might not benefit from longacting beta2-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting beta2-agonists in combination with inhaled corticosteroids.
Asthmatics were stratified by ADRB2 genotype in two studies to assess the effects of inhaled corticosteroids plus longacting beta2-agonists on asthma exacerbations. In study 1 (double-blind), 2250 asthmatics were randomly assigned to budesonide plus formoterol maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol for 6 months. Study 2 (open-label) consisted of 405 asthmatics and compared an adjustable regimen of budesonide plus formoterol with fixed-dose budesonide plus formoterol and fixed-dose fluticasone plus salmeterol for 7 months. The relation between ADRB2 polymorphism, severe asthma exacerbations, and other asthma outcomes was analysed. Primary endpoints for studies 1 and 2 were severe asthma exacerbation and asthma control as assessed by measures of exacerbations, respectively.
In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes.
Since we showed no pharmacogenetic effect of ADRB2 variation on therapeutic response in asthma, patients, irrespective of their genotype, can continue to receive inhaled corticosteroids plus longacting beta2-agonists.
新证据表明，β2肾上腺素能受体（ADRB2）第16位氨基酸为精氨酸纯合子的哮喘患者可能无法从长效β2激动剂治疗中获益。因此，我们研究了ADRB2基因多态性是否会影响长效β2激动剂与吸入性糖皮质激素联合使用的疗效。
在两项研究中，根据ADRB2基因型对哮喘患者进行分层，以评估吸入性糖皮质激素加长效β2激动剂对哮喘急性加重的影响。在研究1（双盲）中，2250名哮喘患者被随机分配接受布地奈德加福莫特罗维持和缓解治疗、固定剂量布地奈德加福莫特罗，或固定剂量氟替卡松加沙美特罗治疗6个月。研究2（开放标签）包括405名哮喘患者，比较了布地奈德加福莫特罗的可调方案与固定剂量布地奈德加福莫特罗以及固定剂量氟替卡松加沙美特罗治疗7个月的效果。分析了ADRB2基因多态性、严重哮喘急性加重和其他哮喘结局之间的关系。研究1和2的主要终点分别是通过急性加重指标评估的严重哮喘急性加重和哮喘控制情况。
在研究1中，Gly16Arg基因型对所有治疗组中发生严重急性加重的参与者百分比没有影响（833名Gly/Gly参与者中有99名[12%]，1028名Gly/Arg参与者中有110名[11%]，361名Arg/Arg参与者中有32名[9%]）。各基因型组之间的次要终点，包括第1秒用力呼气量、呼气峰值流速、按需使用药物情况以及夜间觉醒次数相似。未记录到ADRB2单倍型与主要和次要终点之间的关联。在研究2中，所有ADRB2基因型的哮喘急性加重频率（168名Gly/Gly参与者中有15名[9%]，169名Gly/Arg参与者中有13名[8%]，67名Arg/Arg参与者中有6名[9%]）和其他研究终点非常相似。
由于我们未发现ADRB2变异对哮喘治疗反应有药物遗传学效应，无论基因型如何，患者均可继续接受吸入性糖皮质激素加长效β2激动剂治疗。
