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Genetic Variation of the β2-Adrenoceptor

Its Functional and Clinical Importance in Bronchial Asthma

  • Practical Pharmacogenomics
  • Published:
American Journal of Pharmacogenomics

Abstract

Asthma is a polygenic disease for which no clear genotype-phenotype relationships have emerged. In contrast, although not associated with the diagnosis of asthma per se, variant forms of the β2-adrenoceptor (β2-AR) gene (ADRB2) display functional effects that may be clinically relevant. Single nucleotide polymorphisms (SNPs) of ADBR2 are common and result in amino acid substitutions at positions 16, 27, and 164 of the receptor as well as position 19 of its 5′ upstream peptide. These SNPs influence receptor function in vitro, although evidence regarding exact relationships is conflicting. This has raised the possibility that phenotypes such as bronchial hyper-responsiveness (BHR) and responses to β2-agonist drugs may be genetically determined. To date, no unequivocal relationships between SNPs and phenotype have been identified. In some studies the Gly16 allele has been associated with increased BHR and asthma severity. In others, the Arg16 allele has been shown to determine acute bronchodilator response and adverse events during long term β2-agonist therapy. The latter may provide the basis for clinical application of this new knowledge. More recently, a small number of frequently occurring, functionally relevant ADRB2 haplotype pairs have been confirmed. These combinations of alleles may be more important in determining genotype/phenotype relationships than individual SNPs, and may explain why earlier investigations have yielded contrasting results. Future studies will be required to clarify the pharmacodynamic effects of ADRB2 haplotypes both in vitro and in vivo.

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References

  1. Martinez FD. Complexities of the genetics of asthma. Am J Respir Crit Care Med 1997; 156 (4 Pt 2): S117–22

    CAS  PubMed  Google Scholar 

  2. Szentivanyi A, Omaha N. The β-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968; 42203–32

    Google Scholar 

  3. Reihsaus E, Innis M, Maclntyre N, et al. Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8(3): 334–9

    CAS  PubMed  Google Scholar 

  4. Hausdorff WP, Caron MG, Lefkowitz RJ. Turning off the signal: desensitization of β-adrenergic receptor function. FASEB J 1990; 4(11): 2881–9

    CAS  PubMed  Google Scholar 

  5. Johnson M. The β-adrenoceptor. Am J Respir Crit Care Med 1998; 158 (5 Pt 3): S146–53

    CAS  PubMed  Google Scholar 

  6. Kobilka BK, Frielle T, Dohlman HG, et al. Delineation of the intronless nature of the genes for the human and hamster β2-adrenergic receptor and their putative promoter regions. J Biol Chem 1987; 262(15): 7321–7

    CAS  PubMed  Google Scholar 

  7. Kobilka BK, Matsui H, Kobilka TS, et al. Cloning, sequencing, and expression of the gene coding for the human platelet α2-adrenergic receptor. Science 1987; 238(4827): 650–6

    Article  CAS  PubMed  Google Scholar 

  8. Schofield PR, Rhee LM, Peralta EG. Primary structure of the human β-adrenergic receptor gene. Nucleic Acids Res 1987; 15(8): 3636

    Article  CAS  PubMed  Google Scholar 

  9. Kobilka BK, Dixon RA, Frielle T, et al. cDNA for the human β2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci U S A 1987; 84(1): 46–50

    Article  CAS  PubMed  Google Scholar 

  10. Yang-Feng TL, Xue FY, Zhong WW, et al. Chromosomal organization of adrenergic receptor genes. Proc Natl Acad Sci U S A 1990; 87(4): 1516–20

    Article  CAS  PubMed  Google Scholar 

  11. Scott MG, Swan C, Wheatley AP, et al. Identification of novel polymorphisms within the promoter region of the human β2-adrenergic receptor gene. Br J Pharmacol 1999; 126(4): 841–4

    Article  CAS  PubMed  Google Scholar 

  12. McGraw DW, Forbes SL, Kramer LA, et al. Polymorphisms of the 5′ leader cistron of the human β2-adrenergic receptor regulate receptor expression. J Clin Invest 1998; 102(11): 1927–32

    Article  CAS  PubMed  Google Scholar 

  13. Parola AL, Kobilka BK. The peptide product of a 5′ leader cistron in the β2-adrenergic receptor mRNA inhibits receptor synthesis. J Biol Chem 1994; 269(6): 4497–505

    CAS  PubMed  Google Scholar 

  14. Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 2000; 97(19): 10483–8

    Article  CAS  PubMed  Google Scholar 

  15. Liggett SB. β2-adrenergic receptor pharmacogenetics. Am J Respir Crit Care Med 2000; 161 (3 Pt 2): S197–201

    CAS  PubMed  Google Scholar 

  16. Xie HG, Stein CM, Kim RB, et al. Frequency of functionally important β2-adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals. Pharmacogenetics 1999; 9(4): 511–16

    CAS  PubMed  Google Scholar 

  17. Davidson S. Research suggests importance of haplotypes over SNPs. Nat Biotechnol 2000; 18(11): 1134–5

    Article  CAS  PubMed  Google Scholar 

  18. Sandford AJ, Pare PD. The genetics of asthma. The important questions. Am J Respir Crit Care Med 2000; 161 (3 Pt 2): S202–6

    CAS  PubMed  Google Scholar 

  19. Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994; 264(5162): 1152–6

    Article  CAS  PubMed  Google Scholar 

  20. Doull IJ, Lawrence S, Watson M, et al. Allelic association of gene markers on chromosomes 5q and 11q with atopy and bronchial hyperresponsiveness. Am J Respir Crit Care Med 1996; 153 (4 Pt 1): 1280–4

    CAS  PubMed  Google Scholar 

  21. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the β2-adrenoceptor and the response to long-term β2-agonist therapy in asthma. Eur Respir J 1998; 11(3): 589–93

    CAS  PubMed  Google Scholar 

  22. Weir TD, Mallek N, Sandford AJ, et al. β2adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma. Am J Respir Crit Care Med 1998; 158(3): 787–91

    CAS  PubMed  Google Scholar 

  23. D’Amato M, Vitiani LR, Petrelli G, et al. Association of persistent bronchial hyperresponsiveness with β2adrenoceptor (ADRB2) haplotypes. A population study. Am J Respir Crit Care Med 1998; 158(6): 1968–73

    PubMed  Google Scholar 

  24. Dewar JC, Wheatley AP, Venn A, et al. 2-adrenoceptor polymorphisms are in linkage disequilibrium, but are not associated with asthma in an adult population. Clin Exp Allergy 1998; 28(4): 442–8

    Article  CAS  PubMed  Google Scholar 

  25. Liggett SB. Pharmacogenetics of β1 and β2adrenergic receptors. Pharmacology 2000; 61(3): 167–73

    Article  CAS  PubMed  Google Scholar 

  26. Moore PE, Laporte JD, Abraham JH, et al. Polymorphism of the β2adrenergic receptor gene and desensitization in human airway smooth muscle. Am J Respir Crit Care Med 2000; 162(6): 2117–24

    CAS  PubMed  Google Scholar 

  27. Ulbrecht M, Hergeth MT, Wjst M, et al. Association of β2adrenoreceptor variants with bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000; 161 (2 Pt 1): 469–74

    CAS  PubMed  Google Scholar 

  28. Green SA, Turki J, Bejarano P, et al. Influence of β2adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995; 13(1): 25–33

    CAS  PubMed  Google Scholar 

  29. Barnes PJ. β-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995; 152(3): 838–60

    CAS  PubMed  Google Scholar 

  30. Green SA, Cole G, Jacinto M, et al. A polymorphism of the human β2adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 1993; 268(31): 23116–21

    CAS  PubMed  Google Scholar 

  31. Green SA, Turki J, Innis M, et al. Amino-terminal polymorphisms of the human β2adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33(32): 9414–19

    Article  CAS  PubMed  Google Scholar 

  32. Chong LK, Chowdry J, Ghahramani P, et al. Influence of genetic polymorphisms in the β2adrenoceptor on desensitization in human lung mast cells. Pharmacogenetics 2000; 10(2): 153–62

    Article  CAS  PubMed  Google Scholar 

  33. Large V, Hellstrom L, Reynisdottir S, et al. Human β2adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte β2adrenoceptor function. J Clin Invest 1997; 100(12): 3005–13

    Article  CAS  PubMed  Google Scholar 

  34. Timmermann B, Mo R, Luft FC, et al. β2adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study. Kidney Int 1998; 53(6): 1455–60

    Article  CAS  PubMed  Google Scholar 

  35. Holloway JW, Dunbar PR, Riley GA, et al. Association of β2adrenergic receptor polymorphisms with severe asthma. Clin Exp Allergy 2000; 30(8): 1097–1103

    Article  CAS  PubMed  Google Scholar 

  36. Martinez FD, Graves PE, Baldini M, et al. Association between genetic polymorphisms of the β2adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997; 100(12): 3184–8

    Article  CAS  PubMed  Google Scholar 

  37. Ramsay CE, Hayden CM, Tiller KJ, et al. Polymorphisms in the β2adrenoreceptor gene are associated with decreased airway responsiveness. Clin Exp Allergy 1999; 29(9): 1195–203

    Article  CAS  PubMed  Google Scholar 

  38. Summerhill E, Leavitt SA, Gidley H, et al. β2adrenergic receptor Argl6/Argl6 genotype is associated with reduced lung function, but not with asthma, in the Hutterites. Am J Respir Crit Care Med 2000; 162 (2 Pt 1): 599–602

    CAS  PubMed  Google Scholar 

  39. Ohe M, Munakata M, Hizawa N, et al. β2adrenergic receptor gene restriction fragment length polymorphism and bronchial asthma. Thorax 1995; 50(4): 353–9

    Article  CAS  PubMed  Google Scholar 

  40. Hopes E, McDougall C, Christie G, et al. Association of glutamine 27 polymorphism of β2adrenoceptor with reported childhood asthma: population based study. BMJ 1998; 316(7132): 64

    Article  Google Scholar 

  41. Turki J, Pak J, Green SA, et al. Genetic polymorphisms of the β2adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995; 95(4): 1635–41

    Article  CAS  PubMed  Google Scholar 

  42. Szefler SJ, Ando R, Cicutto LC, et al. Plasma histamine, epinephrine, cortisol, and leukocyte β-adrenergic receptors in nocturnal asthma. Clin Pharmacol Ther 1991; 49(1): 59–68

    Article  CAS  PubMed  Google Scholar 

  43. Liggett SB. Polymorphisms of the β2adrenergic receptor and asthma. Am J Respir Crit Care Med 1997; 156 (4 Pt 2): S156–62

    CAS  PubMed  Google Scholar 

  44. Hargreave FE, Ryan G, Thomson NC, et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol 1981; 68(5): 347–55

    Article  CAS  PubMed  Google Scholar 

  45. Hall IP, Wheatley A, Wilding P, et al. Association of Glu 27 β2adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995; 345(8959): 1213–14

    Article  CAS  PubMed  Google Scholar 

  46. Fowler SJ, Dempsey OJ, Sims EJ, et al. Screening for bronchial hyperresponsiveness using methacholine and adenosine monophosphate. Relationship to asthma severity and β2receptor genotype. Am J Respir Crit Care Med 2000; 162 (4 Pt 1): 1318–22

    CAS  PubMed  Google Scholar 

  47. Taylor DR, Sears MR. Is chronic use of β2agonists detrimental in the treatment of asthma? In: Gimbycz M, O’Connor B editors. Asthma: epidemiology, anti-inflammatory therapy and future trends. lag/Switzerland: Birkhauser 2000: 57–72

    Chapter  Google Scholar 

  48. Dewar JC, Wilkinson J, Wheatley A, et al. The glutamine 27 β2drenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J Allergy Clin Immunol 1997; 100(2): 261–5

    Article  CAS  PubMed  Google Scholar 

  49. Lima JJ, Thomason DB, Mohamed MH, et al. Impact of genetic polymorphisms of the β2adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 1999; 65(5): 519–25

    Article  CAS  PubMed  Google Scholar 

  50. Cockcroft JR, Gazis AG, Cross DJ, et al. β2adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000; 36(3): 371–5

    Article  CAS  PubMed  Google Scholar 

  51. Cockcroft DW, Swystun VA. Functional antagonism: tolerance produced by inhaled β2agonists. Thorax 1996; 51(10): 1051–6

    Article  CAS  PubMed  Google Scholar 

  52. Hancox RJ, Aldridge RE, Cowan JO, et al. Tolerance to β-agonists during acute bronchoconstriction. Eur Respir J 1999; 14(2): 283–7

    Article  CAS  PubMed  Google Scholar 

  53. Jones S, Cowan J, Flannery E, et al. Bronchodilator tolerance during acute bronchoconstriction in patients taking formoterol. Eur Respir J 2001; 17: 368–73

    Article  CAS  PubMed  Google Scholar 

  54. Tan S, Hall IP, Dewar J, et al. Association between β2adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350(9083): 995–9

    Article  CAS  PubMed  Google Scholar 

  55. Lipworth BJ, Hall IP, Aziz I, et al. β2adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2agonist therapy. Clin Sci (Colch) 1999; 96(3): 253–9

    Article  CAS  Google Scholar 

  56. Lipworth BJ, Hall IP, Tan S, et al. Effects of genetic polymorphism on ex vivo and in vivo function of β2adrenoceptors in asthmatic patients. Chest 1999; 115(2): 324–8

    Article  CAS  PubMed  Google Scholar 

  57. Taylor DR, Hancox RJ, McRae W, et al. The influence of polymorphism at position 16 of the β2adrenoceptor on the development of tolerance to β-agonist. J Asthma 2000; 37(8): 691–700

    Article  CAS  PubMed  Google Scholar 

  58. Taylor DR, Drazen JM, Herbison GP, et al. Asthma exacerbations during long term β-agonist use: influence of β2adrenoceptor polymorphism. Thorax 2000; 55(9): 762–7

    Article  CAS  PubMed  Google Scholar 

  59. Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the β2adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000; 162(1): 75–80

    CAS  PubMed  Google Scholar 

  60. Jones SL, Taylor DR. Excessive use of inhaled salbutamol: the potential benefits of dose-reduction. A case report. N Z Med J 1999; 112(1100): 448–50

    CAS  PubMed  Google Scholar 

  61. Eisenstadt WS, Nicholas SS. The adverse effect of adrenergic aerosols in bronchial asthma. Ann Allergy 1969; 27(6): 283–8

    CAS  PubMed  Google Scholar 

  62. Reisman RE. Asthma induced by adrenergic aerosols. J Allergy 1970; 46(3): 162–77

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

MK is a Senior Research Fellow of the Health Research Council of New Zealand.

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Authors and Affiliations

  1. Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    D. Robin Taylor (Associate Professor)

  2. Gene Structure and Function Laboratory, Department of Pathology, Christchurch School of Medicine, University of Otago, Christchurch, New Zealand

    Martin A. Kennedy

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  1. D. Robin Taylor
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  2. Martin A. Kennedy
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Correspondence to D. Robin Taylor.

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Taylor, D.R., Kennedy, M.A. Genetic Variation of the β2-Adrenoceptor. Am J Pharmacogenomics 1, 165–174 (2001). https://doi.org/10.2165/00129785-200101030-00002

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