Skip to main content
SpringerLink
Log in

β2-Adrenergic Receptor Haplotype may be Associated with Susceptibility to Desensitization to Long-Acting β2-Agonists in COPD Patients

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Purpose

Τhat β2-adrenergic receptor (β2AR) haplotypes may play a key role in clinical response to β2-agonists and haplotype Cys-19Gly16Gln27 (CysGlyGln) is reported to be associated with desensitization of β2AR to β-agonists in lymphocytes isolated from patients with asthma and septic shock. We sought to determine whether haplotypic variation of the β2AR affects the functional outcomes of long-acting β2-agonist (LABA) treatment for chronic obstructive pulmonary disease (COPD) when used as monotherapy.

Methods

Treatment-naïve patients with COPD (n = 36) were prospectively treated with two kinds of LABA—inhaled salmeterol and transdermal tulobuterol patch—for 12 weeks in crossover study, and changes in pulmonary function data and 6-minute walk distance (6MWD) were compared between groups stratified by the CysGlyGln.

Results

Frequencies of haplotype and diplotype for the CysGlyGln were 0.51 and 0.36, respectively. The individuals homozygous for CysGlyGln showed less improvement in FEV1, %FEF25−75 %, and IC/TLC than those with 0 or 1 copy of CysGlyGln after treatment with both LABAs despite initial bronchodilator responses to albuterol being similar in these groups. The response in these parameters was not significantly different between two types of LABA. Overall changes in 6MWD in individuals with 2 copies of CysGlyGln versus 0 or 1 copy for salmeterol were 2.8 and 11 m, and for tulobuterol were −1.3 and 16 m, respectively.

Conclusions

Homozygous haplotype for the CysGlyGln of β2AR may be associated with susceptibility to desensitization to LABA in patients with COPD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. National Heart, Lung, and Blood Institute/World Health Organization (2010) Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease (GOLD): NHLBI/WHO workshop report. NIH Publication, National Institutes of Health, Bethesda

  2. Taylor DR (2007) beta-Adrenergic receptor polymorphisms: relationship to the beta-agonist controversy and clinical implications. Expert Opin Pharmacother 18:3195–3203

    Article  Google Scholar 

  3. Cazzola M, Calzetta L, Matera MG (2011) β2-adrenoceptor agonists: current and future direction. Br J Pharmacol 163:4–17

    Article  PubMed  CAS  Google Scholar 

  4. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, Liggett SB (2000) Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 97:10483–10488

    Article  PubMed  CAS  Google Scholar 

  5. Hawkins GA, Tantisira K, Meyers DA, Ampleford EJ, Moore WC, Klanderman B, Liggett SB, Peters SP, Weiss ST, Bleecker ER (2006) Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study. Am J Respir Crit Care Med 174:1101–1109

    Article  PubMed  CAS  Google Scholar 

  6. Panebra A, Wang WC, Malone MM, Pitter DRG, Weiss ST, Hawlins GA, Liggett SB (2010) Common ADRB2 haplotypes derived from 26 polymorphic sites direct β2-adrenergic receptor expression and regulation phenotypes. PLoS One 5:e11819

    Article  PubMed  Google Scholar 

  7. 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

    Article  PubMed  CAS  Google Scholar 

  8. 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

    Article  PubMed  CAS  Google Scholar 

  9. Dishy V, Sofowora GG, Xie HG, Kim RB, Byrne DW, Stein CM, Wood AJ (2001) The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 345:1030–1035

    Article  PubMed  CAS  Google Scholar 

  10. Turki J, Pak J, Green SA, Martin RJ, Liggett SB (1995) Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 95:1635–1641

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, Cooper DM, Fahy JV, Fish JE, Ford JG, Kraft M, Kunselman S, Lazarus SC, Lemanske RF, Martin RJ, McLean DE, Peters SP, Silverman EK, Sorkness CA, Szefler SJ, Weiss ST, Yandava CN (2000) The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 162:75–80

    PubMed  CAS  Google Scholar 

  13. Wechsler ME, Lehman E, Lazarus SC et al (2006) beta-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 173:519–526

    Article  PubMed  CAS  Google Scholar 

  14. Bleecker ER, Nelson HS, Kraft M, Corren J, Meyers DA, Yancey SW, Anderson WH, Emmett AH, Ortega HG (2010) Beta2-receptor polymorphisms in patients receiving salmeterol with or without fluticasone propionate. Am J Respir Crit Care Med 181:676–687

    Article  PubMed  CAS  Google Scholar 

  15. Taylor DR, Epton MJ, Kennedy MA et al (2005) Bronchodilator response in relation to β2-adrenoreceptor haplotype in patients with asthma. Am J Respir Crit Care Med 172:700–703

    Article  PubMed  Google Scholar 

  16. Oostendorp J, Postma DS, Volders H, Jongepier H, Kauffman HF, Boezen HM, Meyers DA, Bleecker ER, Nelemans SA, Zaagsma J, Meurs H (2005) Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes. Am J Respir Crit Care Med 172:322–328

    Article  PubMed  Google Scholar 

  17. Nakada TA, Russell JA, Boyd JH, Aguirre-Hernandez R, Thain KR, Thair SA, Nakada E, McConechy M, Walley KR (2010) beta2-Adrenergic receptor gene polymorphism is associated with mortality in septic shock. Am J Respir Crit Care Med 181:143–149

    Article  PubMed  CAS  Google Scholar 

  18. Bleecker ER, Yancey SW, Baitinger LA et al (2006) Salmeterol response is not affected by β2-adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 118:809–816

    Article  PubMed  CAS  Google Scholar 

  19. Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M (2007) Effect of ADRB2 polymorphisms on response to long-acting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 370:2118–2125

    Article  PubMed  CAS  Google Scholar 

  20. Sugawara T, Nanjo Y, Yamazaki M, Higashihara K, Tsuda Y, Mochizuki H, Noguchi T, Takahashi H (2009) Comparison of adherence and efficacy between inhaled salmeterol and transdermal tulobuterol patch in elderly COPD patients. J Am Geriatr Soc 57:919–920

    Article  PubMed  Google Scholar 

  21. Lipworth BJ, Hall IP, Aziz I, Tan KS, Wheatley A (1999) Beta2-adrenoreceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta2-agonist therapy. Clin Sci (Lond) 96:253–259

    Article  CAS  Google Scholar 

  22. Munakata M, Harada Y, Ishida T, Saito J, Nagabukuro A, Matsushita H, Koga N, Ohsaki M, Imagawa K, Shiratsuchi T (2006) Molecular-based haplotype analysis of the beta 2-adrenergic receptor gene (ADRB2) in Japanese asthmatic and non-asthmatic subjects. Allergol Int 55:191–198

    Article  PubMed  CAS  Google Scholar 

  23. Kay LJ, Rostami-Hodjegan A, Suvarna SK, Peachell PT (2007) Influence of beta2-adrenoceptor gene polymorphisms on beta2-adrenoceptor-mediated responses in human lung mast cells. Br J Pharmacol 152(3):323–331

    Article  PubMed  CAS  Google Scholar 

  24. Silverman EK, Kwiatkowski DJ, Sylvia JS, Lazarus R, Drazen JF, Lange C, Liard NM, Weiss ST (2003) Family-based association analysis of β-adrenergic receptor polymorphisms in the childhood asthma management program. J Allergy Clin Immunol 112:870–876

    Article  PubMed  CAS  Google Scholar 

  25. Taylor DR, Hall IP (2007) ADRB2 polymorphisms and beta2 agonists. Lancet 370:2975–2976

    Google Scholar 

  26. Wechsler ME, Lunselman S, Chincillli VM et al (2009) Effect of β2-adrenoceptor polymorphism on response to long-acting β2-agonist in asthma (LARGE trial): a genotype-stratified, randomized, placebo-controlled, crossover trial. Lancet 374:1754–1764

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No source of funding was used to assist in the preparation of this manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Respiratory Medicine, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan

    Hideaki Mochizuki, Yuta Nanjo, Eriko Kawate, Mariko Yamazaki, Yasunari Tsuda & Hideki Takahashi

Authors
  1. Hideaki Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuta Nanjo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eriko Kawate
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariko Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasunari Tsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideki Takahashi.

Additional information

Clinical trial registered with www.umin.ac.jp/ctr/index/htm (UMIN000002629).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mochizuki, H., Nanjo, Y., Kawate, E. et al. β2-Adrenergic Receptor Haplotype may be Associated with Susceptibility to Desensitization to Long-Acting β2-Agonists in COPD Patients. Lung 190, 411–417 (2012). https://doi.org/10.1007/s00408-012-9387-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-012-9387-7

Keywords

Search

Navigation