Discussion
The treatment options for asthma have substantially increased. Presently, inhaled beta 2 adrenergic receptor agonists, inhaled corticosteroids, leukotriene modifiers, inhaled anticholinergics, theophylline, and immunosuppressive agents are the most common medicines for the treatment of asthma [26]. With the development of small molecule therapy and various biological agents, biologic therapies such as genetic therapy will play an important role in treating asthma [26]. Among these, short-acting beta-2 agonists (SABA) are the primary choices for the therapy of acute asthma [14, 27]. SABA selectively bind to and activate ADRB2 within the cell membrane and relax airway smooth muscle, dilate the bronchi and improve airflow achieving remission of symptoms[28].
However, there is considerable variability in inhaled SABA responsiveness, 70-80% of this can be due to differences in genetic basis [5], and part of the variability may also be explained by poor compliance, irregular medication and incorrect drug selection etc [29]. Many pharmacogenetics and pharmacogenomics studies [26, 30] have been performed for assessing the association between candidate genes and the response to SABA. A significant heterogeneity has been observed in response to salbutamol [31], and ADRB2 gene could be responsible for this which was cloned by Kobilka et al.[32] in 1987 located on human chromosome 5q31-32, a region that may be linked with asthma and atopy. The ADRB2polymorphisms change the ADRB2 amino acids sequence and may alter receptor function leading to the individual variability in response to salbutamol [9].
Predicting patients who are likely to respond well to salbutamol will be significant to the further development of personalized treatment. A number of studies [13, 20] have evaluated the relationship between ADRB2 polymorphisms (Arg16Gly, Gln27Glu) and salbutamol response. However, the results of these studies are contradictory, probably contributed by ethnic and environmental differences and the varying clinical management methods between countries.
Thus, we conducted a meta-analysis to further quantitatively investigate the effect of the ADRB2 polymorphisms (Arg16Gly, Gln27Glu) on salbutamol responsiveness. Considering different age groups might affect salbutamol responsiveness and ethnicity may be one of the factors leading to different distribution of genetic polymorphism[33-35], we performed subgroup analyses according to age and ethnicity. We observed that as for Arg16Gly polymorphism the patients especially in adult asthmatics with the AG genotype in comparison with the AA or GG+AA genotypes had a better response to salbutamol, which indicated that salbutamol may be more effective for patients with the AG genotype. The findings are consistent with the study performed by Mohamed-Hussein et al.[13] which revealed that 75% of patients with the AG genotype were positive responders, and 81% of patients carrying the GG genotype were poor responders. Similar to these results, TellerĂ­aet al. [17] demonstrated that G allele carriers and especially patients with the AG genotype were overrepresented among subjects with good responses, while patients with the A allele were more likely to represent in the group with tachyphylaxis. In addition, Martinez et al.[20] revealed that compared to those with the GG genotype, patients carrying the AG genotype were 2.3 times more likely to response to salbutamol, whereas contrary to our results, patients with the AA genotype were 5.3 times more likely to have a good response.
However, our conclusions are inconsistent with the findings showed in the previous meta-analysis performed by Finkelstein et al in 2009[36], demonstrating that patients with the AA genotype at Arg16Gly polymorphism had a positive response to salbutamol compared to those with the AG or GG genotypes. There may be the following reasons: we excluded one study [7]selected in the previous meta-analysis but might not meet the quality criteria of the Q-Genie tool which was used in this study; included more studies up to August 2020 and applied more genetic models appropriately. Consistent with the previous meta-analysis [36], our findings indicated no effect of the Gln27Glu polymorphism on salbutamol responsiveness.
Some limitations still exist in this meta-analysis: (1) Our study mainly focused on the most common variants (Arg16Gly, Gln27Glu), other polymorphisms that have also been studied in the ADRB2 gene[26, 37, 38] could be reported to evaluate the genetic effect of ADRB2 on salbutamol response; (2) The number of articles included in this study and the sample size particularly for the Gln27Glu polymorphism are relatively small. Thus if more datasets are available, renewed analyses could be considered; and (3) Our research was based on dichotomous data, while continuous outcomes showing the percentage change in FEV1 before and after salbutamol inhalation were not collected.