Abstract
The aims of this study were: (1) to find associations of asthma with single-nucleotide polymorphisms (SNPs) within theADRB2 gene: Arg16Gly, Gln27Glu, −1023 G/A, −367 T/C, −47 C/T ; (2) to define linkage disequilibrium in the gene region, basing on the analyzed SNPs; and (3) to analyze the importance ofADRB2 polymorphism for response to bronchodilator drugs in children diagnosed with bronchial asthma. We compared 113 asthmatic children and 123 healthy subjects from the Polish population. Genotyping was performed by PCR-RFLP. We found an association of the A allele of −1023A/GADRB2 polymorphism with asthma (P = 0.024). No significant associations with other SNPs were detected. Moderate linkage was found between Gln27Glu and −47C/T polymorphisms in linkage disequilibrium analysis (D’ = 0.85,r 2 = 0.429, LOD = 31.97). No significant differences were found in haplotype frequencies in comparison to the control group, implicating that they are not associated with susceptibility to asthma in the analyzed population. There was no significant correlation between the analyzed SNPs of theADRB2 gene and the response to β2-agonists. This is the first report providing suggestive evidence for association of —1023A/GADRB2 polymorphism with an increased risk of asthma. The analyzed SNPs may not play a major role in response to β2-agonists in asthmatic children.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barrett JC, Fry B, Maller J Daly MJ, 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
Bleecker ER, Yancey SW, Baitinger LA, Edwards LD, Klotsman M, Anderson WH, Dorinsky PM, 2006. Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 118: 809–816.
Boege F, Ward M, Jurss R, Hekman M Helmreich EJ, 1988. Role of glycosylation for beta 2-adrenoceptor function in A431 cells. J Biol Chem 263: 9040–9049.
Cavalli-Sforza L, 1994. The history and geography of human genes. Princeton University Press: New Jersey.
Contopoulos-Ioannidis DG, Manoli EN Ioannidis JP, 2005. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol 115: 963–972.
Dewar JC, Wheatley AP, Venn A, Morrison JF, Britton J Hall IP, 1998. Beta2-adrenoceptor polymorphisms are in linkage disequilibrium, but are not associated with asthma in an adult population. Clin Exp Allergy 28: 442–448.
Green SA, Turki J, Hall IP Liggett SB, 1995. Implications of genetic variability of human beta 2-adrenergic receptor structure. Pulm Pharmacol 8: 1–10.
Green SA, Turki J, Innis M Liggett SB, 1994. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 33: 9414–9419.
Johnatty SE, Abdellatif M, Shimmin L, Clark RB, Boerwinkle E, 2002. Beta 2 adrenergic receptor 5’ haplotypes influence promoter activity. Br J Pharmacol 137: 1213–1216.
Joos L, Pare PD Sandford AJ, 2001. beta(2)-adrenergic receptor polymorphisms and asthma. Curr Opin Pulm Med 7: 69–74.
Kukreti R, Bhatnagar P, CBR, Gupta S, Madan B, Das C, et al. 2005. Beta(2)-adrenergic receptor polymorphisms and response to salbutamol among Indian asthmatics*. Pharmacogenomics 6: 399–410.
Lee DK, Currie GP, Hall IP, Lima JJ Lipworth BJ, 2004. The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol 57: 68–75.
Liggett SB, 2000. The pharmacogenetics of beta2-adrenergic receptors: relevance to asthma. J Allergy Clin Immunol 105(2 Pt 2): S487–92.
Lipworth B, Koppelman GH, Wheatley AP, Le Jeune I, Coutie W, Meurs H, et al. 2002. Beta2 adrenoceptor promoter polymorphisms: extended haplotypes and functional effects in peripheral blood mononuclear cells. Thorax 57: 61–66.
Martinez FD, Graves PE, Baldini M, Solomon S Erickson R, 1997. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 100: 3184–3188.
McGraw DW, Forbes SL, Kramer LA Liggett SB, 1998. Polymorphisms of the 5’ leader cistron of the human beta2-adrenergic receptor regulate receptor expression. J Clin Invest 102: 1927–1932.
Migita O, Noguchi E, Jian Z, Shibasaki M, Migita T, Ichikawa K, Matsui A Arinami T, 2004. ADRB2 polymorphisms and asthma susceptibility: transmission disequilibrium test and meta-analysis. Int Arch Allergy Immunol 134: 150–157.
Miller SA, Dykes DD Polesky HF, 1988. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215.
Moore PE, Laporte JD, Abraham JH, Schwartzman IN, Yandava CN, Silverman ES, et al. 2000. Polymorphism of the beta(2)-adrenergic receptor gene and desensitization in human airway smooth muscle. Am J Respir Crit Care Med 162: 2117–2124.
Parola AL Kobilka BK, 1994. The peptide product of a 5’ leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis. J Biol Chem 269: 4497–4505.
Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, Meyers DA, Levitt RC, 1995. Genetic susceptibility to asthma: bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 333: 894–900.
Rands E, Candelore MR, Cheung AH, Hill WS, Strader CD, Dixon RA, 1990. Mutational analysis of beta-adrenergic receptor glycosylation. J Biol Chem 265: 10759–10764.
Reihsaus E, Innis M, MacIntyre N, Liggett SB, 1993. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 8: 334–339.
Scott MG, Swan C, Jobson TM, Rees S Hall IP, 1999. Effects of a range of beta2 adrenoceptor agonists on changes in intracellular cyclic AMP and on cyclic AMP-driven gene expression in cultured human airway smooth muscle cells. Br J Pharmacol 128: 721–729.
Szczepankiewicz A, Breborowicz A, Skibinska M, Wilkosc M, Tomaszewska M, Hauser J, 2007. Association analysis of brain-derived neurotrophic factor gene polymorphisms in asthmatic children. Pediatr Allergy Immunol 18: 293–297.
Tan S, Hall IP, Dewar J, Dow E Lipworth B, 1997. Association between beta 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 350: 995–999.
Telleria JJ, Blanco-Quiros A, Muntion S, Antonio Garrote J, Arranz E, Armentia A, Diez I Castro J, 2006. Tachyphylaxis to beta2-agonists in Spanish asthmatic patients could be modulated by beta2-adrenoceptor gene polymorphisms. Respir Med 100: 1072–1078.
Tsai HJ, Shaikh N, Kho JY, Battle N, Naqvi M, Navarro D, et al. 2006. Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics. Hum Genet 119: 547–557.
Wechsler ME, Lehman E, Lazarus SC, Lemanske RF, Jr., Boushey HA, Deykin A, et al. 2006. beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 173: 519–526.
Westland R, van Veen A, Jansen HM, Jonkers RE Wierenga EA, 2004. Limited impact of multiple 5’ single-nucleotide polymorphisms on the transcriptional control of the human beta 2-adrenoceptor gene. Immunogenetics 56: 625–630.
Wills-Karp M Ewart SL, 2004. Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet 5: 376–387.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Szczepankiewicz, A., Bręborowicz, A., Sobkowiak, P. et al. Role ofADRB2 gene polymorphism in asthma and response to β2-agonists in Polish children. J Appl Genet 50, 275–281 (2009). https://doi.org/10.1007/BF03195683
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF03195683