ADRB2 GENE POLYMORPHISMS AND SALBUTAMOL
RESPONSIVENESS IN SERBIAN CHILDREN WITH ASTHMA
Jovicic N, Babic T, Dragicevic S, Nestorovic B, Nikolic A
*Corresponding Author: Dr. Nevena Jovicic, Department of Pulmonology and Allergology, University Children’s Hospital,
Tirsova 10, 11000 Belgrade, Serbia. Tel: +38-164-115-6721. Fax: +38-111-268-5378. E-mail: jovicic.nevena@gmail.com
page: 33
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DISCUSSION
The main finding of the study was the association
of the +46G allele in the ADRB2 gene with a mild form
of asthma and better response to salbutamol. The finding
that carriers of the ADRB2 +46G allele tended to develop
a mild form of asthma was in correlation with findings of
other studies. In meta-analysis of 28 studies, authors concluded
that carriers of the +46AA genotype had a higher
risk of developing severe and nocturnal asthma than carriers
of the +46GG genotype [14]. On the other hand, an
Egyptian study in school-age children with asthma had
shown an association of the +46GA genotype with severe
asthma [15].
Genetic variation in the ADRB2 gene may have
important effect on modulating responses to inhaled β2-
agonists as the mainstay of asthma therapy. Previous studies
have dealt with +46A>G and +79C>G polymorphisms
and their impact on differential agonist-stimulated downregulation
of the receptor in transfected cells, including
airway smooth muscle cells in humans and which can
be associated with a different bronchodilator response to
β2-agonists [10,11,16-19]. In our study, the presence of
the +46G allele in the ADRB2 gene was associated with
a better response to the bronchodilator effect of inhaled
short-acting β2-agonists (salbutamol). As noted above, our
study showed the association of this +46GG genotype with
the phenotype of mild asthma. However, it was noticed
in the subgroup of asthmatic children with the +46A>G
polymorphism, the highest percentage of children with
severe asthma were the carriers of the +46GG genotype.
As this genotype was associated with the best response to
bronchodilators, we can expect a good clinical response to
salbutamol in this subgroup of patients (the severe asthma
phenotype who are carriers of the +46GG genotype). Monitoring
of FEV1 following administration of salbutamol
as a response measure for bronchodilator use is the most
objective, immediate and most frequently studied pulmonary
function parameter in the previous trials [13]. The
relationship between ADRB2 genotypes and response to
inhaled β2-agonists was controversial and discordant findings
had been reported. In early studies, authors showed
better bronchodilator response in children with the +46GG
genotype [20]. Later, several studies showed similar results
[21,22]. The meta-analysis showed a significant association
between better therapeutic response to inhaled
β2-agonist and the +46GG genotype [6]. However, a few
studies have shown opposite results. Carroll [23] found
that children with the +46AA genotype had a more rapid
response to inhaled β2-agonist. Examining ethnic differences,
Choudhry et al. [24] showed better salbutamol
response in Mexican children with the +46AA genotype
but not in the Puerto Rican ethnic group. The only study
conducted in Serbia included adults and showed a better
bronchodilator response in carriers of the +79C allele in
asthmatic patients younger than 50 years [12]. Some larger
studies have shown the absence of association of genetic
variation of ADRB2 and the response to inhaled β2-agonist
[25,26]. Several reasons may explain the discordant results
reported by different authors. The studies were not coherent
in terms of age of the subjects and the severity of their
illness. Authors had also used different β2-agonists and
different outcome measures to assess drug responsiveness
[27]. Some authors studied the associations of certain
haplotypes with therapeutic response to a particular drug
and made a conclusion by which different results can be
explained by specific combinations of polymorphisms
that are most commonly inherited together, rather than
individual polymorphisms.
The main limitation of our study was the relatively
small number of subjects. On the other hand, we had applied
strict criteria for the selection of subjects to avoid the
results being influenced by any of the non genetic factors.
Children with asthma and other associated illness were
not included in the study. The study included children of
Serbian ethnicity, although in Serbia there are members
of other ethnic communities (e.g., Hungarian, Croatian,
Roma). We cannot exclude the possibility that adjacent
genes or other polymorphisms within the promoter and
coding regions of the ADRB2 gene can contribute to the
results. The fact is that there are a multitude of polymorphisms
of the ADRB2 gene and a certain set of alleles are
more likely to be inherited together as a block. The protective
effect of one polymorphism may mask the adverse
effect of another polymorphism when inherited together.
Hence, association of ADRB2 haplotypes with bronchodilator
response may be more relevant than single polymorphisms.
For the extrapolation of these results in our
population, a larger sample is needed and ethnicity should be taken into consideration. The study covered the acute
use of short-acting bronchodilators and the results cannot
be correlated in light of the effects of their long-term use
or, possibly, effects of long-acting bronchodilators.
To conclude, the polymorphism +46A>G of the
ADRB2 gene may be a determinant of asthma severity
and the +46G allele is a potential predictive marker of
response to salbutamol in Serbian children with asthma.
The results of our study can help establish future research
strategies regarding the role of the ADRB2 gene in asthma
and response to therapy, and are of potential use for personalized
asthma treatment in children.
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