Relevance. The relevance of the study of Arg16Gly polymorphism of the β2-adrenoceptor (β2-AR) gene is due to the fact that a number of studies have proven its role in the development of bronchial asthma (BA), bronchial hyperactivity, the effectiveness of basic treatment. However, these associations show low reproducibility in various studies, so the question of the possibility of clinical application of the results of genetic testing for Arg16Gly polymorphic variant of the β2-AR gene remains unanswered. The main reasons why the clinical significance of this polymorphism is not confirmed in various studies are - population heterogeneity, insufficient sample size, improper characterization of comparison groups.
Objective: to study the association of Arg16Gly polymorphism in the β2-adrenoceptor gene with BA clinical course taking into account the age of onset.
Materials and methods. We examined 553 BA patients (group I included 282 patients with late-onset asthma and group II included 271 patients with early-onset asthma) and 95 apparently healthy individuals. The study has been approved by the Bioethics Committee of Medical Institute of Sumy State University. Arg16Gly polymorphism in the β2-АR gene (rs1042713) was determined using polymerase chain reaction-restriction fragment length polymorphism analysis. Statistical analysis of obtained results was performed using SPSS–17 program.
Results. There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the β2-AR gene depending on asthma severity with no regard for the age of onset (χ2 = 5.14; p = 0.27). With regard for the age of onset, we found out that early-onset BA was linked to a difference in genotype distribution for this polymorphic variant in patients with severe and non-severe course (χ2 = 14.76; р = 0.001). The frequency of Gly/Gly genotype was higher in patients with severe course (41.4%) as compared to patients with mild course (16.4%), while the frequency of Arg/Arg (32.9%) and Arg/Gly (50.7%) genotypes was higher in patients with mild asthma as compared to patients with severe course (24.3% and 34.3%). There was no significant difference in the distribution of genotypes in patients with late-onset asthma with regard to course severity (χ2 = 4.94; p = 0.084).
The relative risk of severe course for early-onset asthma was 3.84 times higher (95% CI 2.11–7.36; p = 0.001) in the recessive model, 2.58 times higher (95% CI 1.53–4,37, p = 0.001) in the dominant model, and 2.16 times (95% CI 1.56–3.04) higher in the additive model. In patients with late-onset asthma, no association was found in all models.
Conclusions. There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the β2-AR gene depending on asthma severity with no regard for the age of onset. When adjusted for the age of onset, the analysis revealed a difference in genotype distribution for this polymorphic variant in patients with severe and non-severe course having early-onset BA (р = 0.001). The frequency of Gly/Gly genotype was higher in patients with severe course as compared to patients with mild course. For patients with late-onset asthma, no differences were found (p = 0.084). Heterozygous and homozygous Gly allele carriers have a higher risk of early-onset asthma only.
Ferreira MA, Mathur R. Vonk JM, Szwajda A, Brumpton B. et al. Genetic Architectures of Childhood and Adult Onset Asthma Are Partly Distinct. Am J Hum Genet. 2019;104(4):665-684. DOI: 10.1016/j.ajhg.2019.02.022
Publisher site: https://www.cell.com/ajhg/fulltext/S0002-9297(19)30067-9
PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451732/
Yates AD, Achuthan P, Akanni W, Allen J, Alvarez-Jarreta J. et al. Ensembl 2020. Nucleic Acids Res. 2020;8(48):D682-D688. DOI: 10.1093/nar/gkz966
Publisher site: https://academic.oup.com/nar/article/48/D1/D682/5613682
PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145704/
Slob EM, Vijverberg SJ, Palmer CN. et al. Pharmacogenetics of inhaled long-acting beta2-agonists in asthma: a systematic review. Pediatric Allergy and Immunology. 2018;29(7):705-14. DOI: 10.1111/pai.12956
Publisher site: https://onlinelibrary.wiley.com/doi/abs/10.1111/pai.12956
Zhang E, Levin AM, Williams LK. How does race and ethnicity effect the precision treatment of asthma? Expert Review of Precision Medicine and Drug Development. Taylor & Francis. 2019;4(6):337-56. DOI: 10.1080/23808993.2019.1690396
PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531627/
Siroux V, González JR, Bouzigon E. et al. Genetic heterogeneity of asthma phenotypes identified by a clustering approach. European Respiratory Journal. 2014;43(2):439-452. DOI: 10.1183/09031936.00032713
Publisher site: https://erj.ersjournals.com/content/43/2/439
Liang SQ, Chen XL, Deng JM, Wei X, Gong C, Chen ZR, et al. Beta-2 adrenergic receptor (ADRB2) gene polymorphisms and the risk of asthma: a meta-analysis of case-control studies. PLoS One. 2014;9(8):1054-1058. DOI: 10.1371/journal.pone.0104488.
PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128804/
Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol. 2005;115(5):963-72. DOI: 10.1016/j.jaci.2004.12.1119
PubMed Central: https://pubmed.ncbi.nlm.nih.gov/15867853/
Guo X., Zheng H., Mao C., Guan E, Si H. An association and meta-analysis study of 4 SNPs from beta-2 adrenergic receptor (ADRB2) gene with risk of asthma in children. Asian Pac J Allergy Immunol. 2016;34(1):11-20. DOI: 10.12932/AP0522.214.171.1246
Turner S., Francis B, Vijverberg S, Pino-Yanes M. et al. Pharmacogenomics in Childhood Asthma Consortium. Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment. J Allergy Clin Immunol. 2016;138(1):107-113. DOI: 10.1016/j.jaci.2015.10.045
PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931969/
Holloway JW, Dunbar PR, Riley GA, Sawyer G M, Fitzharris PF, Pearce N, Gros GSL, Beasley R. Association of beta2-adrenergic receptor polymorphisms with severe asthma. Clin Exp Allergy. 2000;30(8):1097-1103. DOI: 10.1046/j.1365-2222.2000.00929.x.
Santillan AA, Camargo CA, Ramirez-Rivera A, et al. Association between b2-adrenoceptor polymorphisms and asthma diagnosis among Mexican adults. J Allergy Clin Immunol. 2003;112:1095-1100. DOI: 10.1016/j.jaci.2003.09.029
Chakova NN., Volovyk NO., Nyiazova SS., Belyaeva L.M., Mikulchik N.V., Buza D.V., Mytko Yu.A. [The role of polymorphic loci Arg16Gly and Gln27Glu of the Adrb2 gene in the pathogenesis of atopic diseases in children of Belarus]. Ymmunopatolohyia, Allerholohyia, Ynfektolohyia. 2017;3:30-35. [in Russian].
Publisher site: http://www.immunopathology.com/ru/article.php?carticle=863
Myronova ZhA., Trofymov VY., Yanchyna ED., Dubina M.V., Ulitina A.S. [Association of beta2-adrenergic receptor gene variants (ADRB2) and bronchial asthma]. Problemy klynycheskoi medytsyny. 2009;1(19):58-61. [in Russian].
Azim A, Freeman A, Lavenu A., Mistry H, Haitchi HM, Newell C, Cheng Y, Thirlwall Y, Harvey M, Barber C, Pontoppidan K, Dennison P, Arshad H, Djukanovic R, Howarth P, Kurukulaaratchy RJ. New perspectives on difficult asthma: sex and age of asthma-onset based phenotypes. J Allergy Clin Immunol Pract. 2020;8(10):3396-3406.e4. DOI: 10.1016/j.jaip.2020.05.053
This work is licensed under a Creative Commons Attribution 4.0 International License.