Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
Clin Exp Allergy. 2021 Sep;51(9):1157-1171. doi: 10.1111/cea.13965. Epub 2021 Jul 20.
The polymorphism Arg16 in β -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27.
We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA.
The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects.
In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β -agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686).
The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.
β-肾上腺素能受体（ADRB2）基因中的 Arg16 多态性与接受长效β-激动剂（LABA）治疗的哮喘儿童的恶化风险增加有关。然而，目前尚不清楚这种增加的风险主要归因于这种单一变体还是密码子 16 和 27 处多态性的单倍型的共同作用。
我们评估了 ADRB2 中密码子 16（Arg16Gly）和 27（Gln27Glu）处多态性的单倍型分析是否与接受吸入皮质类固醇（ICS）加 LABA 治疗的患者的哮喘恶化风险相关。
该研究使用了参与多民族儿童哮喘药物基因组学（PiCA）联盟的 10 项独立研究（n=5903）的数据。哮喘恶化定义为在研究访问/入组前的过去 6 或 12 个月内，与哮喘相关的口服皮质类固醇或住院/急诊就诊。使用 haplo.stats 包按年龄和性别调整，按研究进行单倍型与哮喘恶化风险之间的关联。使用逆方差加权法假设随机效应进行荟萃分析。
在接受 ICS 和 LABA 治疗的患者（n=832，年龄：3-21 岁）中，Arg16/Gln27 与 Gly16/Glu27（OR：1.40，95%CI：1.05-1.87，I=0.0%）和 Arg16/Gln27 与 Gly16/Gln27（OR：1.43，95%CI：1.05-1.94，I=0.0%），但不是 Gly16/Gln27 与 Gly16/Glu27（OR：0.99，95%CI：0.71-1.39，I=0.0%），与哮喘恶化风险增加显著相关。敏感性分析表明，在其他治疗类别（按需短效β-激动剂[n=973]、ICS 单药治疗[n=2623]、ICS 加白三烯受体拮抗剂[LTRA；n=338]或 ICS 加 LABA 加 LTRA[n=686]）中，ADRB2 单倍型与哮喘恶化之间没有显著关联。
ADRB2 Arg16 单倍型，可能主要由 Arg16 驱动，增加了接受 ICS 加 LABA 治疗的患者哮喘恶化的风险。这一发现可能对基于 ADRB2 基因型的治疗有益，这可能改善哮喘患者的临床结局。
