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

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.



Number 21
VOL. 21 (1), 2018
Number 21
VOL. 21, 2018 Accepted articles (Accepted, unedited articles, published online and can be cited. The final edited and printed version of the manuscript will appear in future)
Number 21
VOL. 21, 2018 Supplement
Number 20
VOL. 20 (2), 2017
Number 20
VOL. 20 (1), 2017
Number 19
VOL. 19 (2), 2016
Number 19
VOL. 19 (1), 2016
Number 18
VOL. 18 (2), 2015
Number 18
VOL. 18 (1), 2015
Number 17
VOL. 17 (2), 2014
Number 17
VOL. 17 (1), 2014
Number 16
VOL. 16 (2), 2013
Number 16
VOL. 16 (1), 2013
Number 15
VOL. 15 (2), 2012
Number 15
VOL. 15, 2012 Supplement
Number 15
Vol. 15 (1), 2012
Number 14
14 - Vol. 14 (2), 2011
Number 14
The 9th Balkan Congress of Medical Genetics
Number 14
14 - Vol. 14 (1), 2011
Number 13
Vol. 13 (2), 2010
Number 13
Vol.13 (1), 2010
Number 12
Vol.12 (2), 2009
Number 12
Vol.12 (1), 2009
Number 11
Vol.11 (2),2008
Number 11
Vol.11 (1),2008
Number 10
Vol.10 (2), 2007
Number 10
10 (1),2007
Number 9
1&2, 2006
Number 9
3&4, 2006
Number 8
1&2, 2005
Number 8
3&4, 2004
Number 7
1&2, 2004
Number 6
3&4, 2003
Number 6
1&2, 2003
Number 5
3&4, 2002
Number 5
1&2, 2002
Number 4
Vol.3 (4), 2000
Number 4
Vol.2 (4), 1999
Number 4
Vol.1 (4), 1998
Number 4
3&4, 2001
Number 4
1&2, 2001
Number 3
Vol.3 (3), 2000
Number 3
Vol.2 (3), 1999
Number 3
Vol.1 (3), 1998
Number 2
Vol.3(2), 2000
Number 2
Vol.1 (2), 1998
Number 2
Vol.2 (2), 1999
Number 1
Vol.3 (1), 2000
Number 1
Vol.2 (1), 1999
Number 1
Vol.1 (1), 1998

 

 


 About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact
 Copyright © Balkan Journal of Medical Genetics 2006