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.