Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Pharmacogenetics of asthma controller treatment

The Pharmacogenomics Journal volume 13, pages 242–250 (2013)Cite this article

Subjects

Abstract

The interpatient variability in response to asthma controllers is significant and associates with pharmacogenomic variability. The goal of the present study was to identify novel variants that associate with response to common asthma controllers: fluticasone, combination of fluticasone + salmeterol and montelukast with single nucleotide polymorphisms (SNPs) in β2-adrenergic receptor, corticosteroid and leukotriene pathway candidate genes. Participants in a large clinical trial of step-down strategies volunteered for this pharmacogenetic study. A total of 169 SNPs in 26 candidate genes were genotyped in 189 Caucasian participants with asthma who took either fluticasone (100 μg bid), fluticasone propionate (100 μg) + salmeterol (50 μg) (FP/Salm) or montelukast (5 or 10 mg) each night for 16 weeks. Primary outcomes were the slopes of plots of Asthma Control Questionnaire (ACQ) scores versus time following randomization; and the percent change in percent predicted FEV1 (ΔFEV1%pred) from enrollment to the end of the study. Associations between SNPs and outcomes were analyzed using general linear models. False discovery rate and Bonferroni corrections were used to correct for multiple comparisons. In all, 16 SNPs in seven genes were significantly associated with outcomes. For FP/Salm, three SNPs in CHRM2 associated with ACQ slope (P=2.8 × 10−5), and rs1461496 in HSPA8 associated with ΔFEV1%pred. For fluticasone, five SNPs in CRHR1 (P=1.9 × 10−4), and three SNPs in COL2A1 associated with ACQ slope and ΔFEV1%pred, respectively. For montelukast, four SNPs in CHRM2 associated with ΔFEV1%pred and predicted an opposite effect compared with fluticasone (P=9 × 10−3). The present study indentified several novel SNPs that associate with response to common asthma controllers, and support further pharmacogenomic study and the use of genetic variants to personalize asthma treatment.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Akinbami LJ, Moorman JE, Liu X . Asthma prevalence, health care use, and mortality: United States, 2005-2009. Natl Health Stat Report 2011; 32: 1–14.

    Google Scholar 

  2. Lima JJ . Genetic influences on response to asthma pharmacotherapy. Expert Rev Clin Pharmacol 2008; 1: 649–660.

    Article  CAS  PubMed  Google Scholar 

  3. Lima JJ . Treatment heterogeneity in asthma: genetics of response to leukotriene modifiers. Mol Diagn Ther 2007; 11: 97–104.

    Article  CAS  PubMed  Google Scholar 

  4. Lima JJ, Blake KV, Tantisira KG, Weiss ST . Pharmacogenetics of asthma. Curr Opin Pulm Med 2009; 15: 57–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Drazen JM, Silverman EK, Lee TH . Heterogeneity of therapeutic responses in asthma. Br Med Bull 2000; 56: 1054–1070.

    Article  CAS  PubMed  Google Scholar 

  6. Wu AC, Tantisira K, Li L, Schuemann B, Weiss S . Repeatability of response to asthma medications. J Allergy Clin Immunol 2009; 123: 385–390.

    Article  PubMed  Google Scholar 

  7. Tantisira KG, Hwang ES, Raby BA, Silverman ES, Lake SL, Richter BG et al. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci USA 2004; 101: 18099–18104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet 2004; 13: 1353–1359.

    Article  CAS  PubMed  Google Scholar 

  9. Wechsler ME, Israel E . beta-adrenergic receptor genotype and response to salmeterol. J Allergy Clin Immunol 2007; 120: 218–219.

    Article  PubMed  Google Scholar 

  10. Wechsler ME, Lehman E, Lazarus SC, Lemanske Jr RF, Boushey HA, Deykin A et al. beta-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173: 519–526.

    Article  CAS  PubMed  Google Scholar 

  11. Klotsman M, York TP, Pillai SG, Vargas-Irwin C, Sharma SS, van den Oord EJ et al. Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics 2007; 17: 189–196.

    Article  CAS  PubMed  Google Scholar 

  12. Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H et al. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med 2006; 173: 379–385.

    Article  CAS  PubMed  Google Scholar 

  13. Telleria JJ, Blanco-Quiros A, Varillas D, Armentia A, Fernandez-Carvajal I, Jesus Alonso M et al. ALOX5 promoter genotype and response to montelukast in moderate persistent asthma. Respir Med 2008; 102: 857–861.

    Article  PubMed  Google Scholar 

  14. American Lung Association Asthma Clinical Research Centers, Peters SP, Anthonisen N, Castro M, Holbrook JT, Irvin CG, Smith LJ et al. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007; 356: 2027–2039.

    Article  Google Scholar 

  15. American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007; 175: 235–242.

    Article  Google Scholar 

  16. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR . Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999; 14: 902–907.

    Article  CAS  PubMed  Google Scholar 

  17. Hankinson JL, Odencrantz JR, Fedan KB . Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med 1999; 159: 179–187.

    Article  CAS  PubMed  Google Scholar 

  18. Guo SW, Thompson EA . Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 1992; 48: 361–372.

    Article  CAS  PubMed  Google Scholar 

  19. Barrett JC . Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc 2009.

  20. Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, de Bakker PI . SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 2008; 24: 2938–2939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rao PV . Statistical Research Methods in the Life Sciences. Duxbury Press: Pacific Grove, CA, 1998.

    Google Scholar 

  22. Storey JD . A Direct Approach to False Discovery Rates. J R Stat Soc Series B Stat Methodol 2002; 64: 479–498.

    Article  Google Scholar 

  23. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Team RDC . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2010.

    Google Scholar 

  25. Tantisira KG, Lazarus R, Litonjua AA, Klanderman B, Weiss ST . Chromosome 17: association of a large inversion polymorphism with corticosteroid response in asthma. Pharmacogenet Genomics 2008; 18: 733–737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Coulson FR, Fryer AD . Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther 2003; 98: 59–69.

    Article  CAS  PubMed  Google Scholar 

  27. Eglen RM, Hegde SS, Watson N . Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996; 48: 531–565.

    CAS  PubMed  Google Scholar 

  28. Mak JC, Barnes PJ . Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis 1990; 141: 1559–1568.

    Article  CAS  PubMed  Google Scholar 

  29. McGraw DW, Forbes SL, Kramer LA, Witte DP, Fortner CN, Paul RJ et al. Transgenic overexpression of beta(2)-adrenergic receptors in airway smooth muscle alters myocyte function and ablates bronchial hyperreactivity. J Biol Chem 1999; 274: 32241–32247.

    Article  CAS  PubMed  Google Scholar 

  30. Baker DG, Don HF, Brown JK . Direct measurement of acetylcholine release in guinea pig trachea. Am J Physiol 1992; 263: L142–L147.

    CAS  PubMed  Google Scholar 

  31. Patel HJ, Barnes PJ, Takahashi T, Tadjkarimi S, Yacoub MH, Belvisi MG . Evidence for prejunctional muscarinic autoreceptors in human and guinea pig trachea. Am J Respir Crit Care Med 1995; 152: 872–878.

    Article  CAS  PubMed  Google Scholar 

  32. Ayala LE, Ahmed T . Is there loss of protective muscarinic receptor mechanism in asthma? Chest 1989; 96: 1285–1291.

    Article  CAS  PubMed  Google Scholar 

  33. Minette PA, Barnes PJ . Prejunctional inhibitory muscarinic receptors on cholinergic nerves in human and guinea pig airways. J Appl Physiol 1988; 64: 2532–2537.

    Article  CAS  PubMed  Google Scholar 

  34. Fernandes LB, Fryer AD, Hirshman CA . M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle. J Pharmacol Exp Ther 1992; 262: 119–126.

    CAS  PubMed  Google Scholar 

  35. Kume H, Kotlikoff MI . Muscarinic inhibition of single KCa channels in smooth muscle cells by a pertussis-sensitive G protein. Am J Physiol 1991; 261: C1204–C1209.

    Article  CAS  PubMed  Google Scholar 

  36. Schramm CM, Arjona NC, Grunstein MM . Role of muscarinic M2 receptors in regulating beta-adrenergic responsiveness in maturing rabbit airway smooth muscle. Am J Physiol 1995; 269: L783–L790.

    CAS  PubMed  Google Scholar 

  37. Chilvers ER, Batty IH, Barnes PJ, Nahorski SR . Formation of inositol polyphosphates in airway smooth muscle after muscarinic receptor stimulation. J Pharmacol Exp Ther 1990; 252: 786–791.

    CAS  PubMed  Google Scholar 

  38. Grandordy BM, Cuss FM, Sampson AS, Palmer JB, Barnes PJ . Phosphatidylinositol response to cholinergic agonists in airway smooth muscle: relationship to contraction and muscarinic receptor occupancy. J Pharmacol Exp Ther 1986; 238: 273–279.

    CAS  PubMed  Google Scholar 

  39. Roffel AF, Elzinga CR, Zaagsma J . Muscarinic M3 receptors mediate contraction of human central and peripheral airway smooth muscle. Pulm Pharmacol 1990; 3: 47–51.

    Article  CAS  PubMed  Google Scholar 

  40. Mullol J, Baraniuk JN, Logun C, Mérida M, Hausfeld J, Shelhamer JH et al. M1 and M3 muscarinic antagonists inhibit human nasal glandular secretion in vitro. J Appl Physiol 1992; 73: 2069–2073.

    Article  CAS  PubMed  Google Scholar 

  41. Okayama M, Mullol J, Baraniuk JN, Hausfeld JN, Feldman B, Merida M et al. Muscarinic receptor subtypes in human nasal mucosa: characterization, autoradiographic localization, and function in vitro. Am J Respir Cell Mol Biol 1993; 8: 176–187.

    Article  CAS  PubMed  Google Scholar 

  42. Ramnarine SI, Haddad EB, Khawaja AM, Mak JC, Rogers DF . On muscarinic control of neurogenic mucus secretion in ferret trachea. J Physiol 1996; 494 (Part 2): 577–586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Proskocil BJ, Fryer AD . Beta2-agonist and anticholinergic drugs in the treatment of lung disease. Proc Am Thorac Soc 2005; 2: 305–310.

    Article  CAS  PubMed  Google Scholar 

  44. Martinez FD . Safety of long-acting beta-agonists--an urgent need to clear the air. N Engl J Med 2005; 353: 2637–2639.

    Article  CAS  PubMed  Google Scholar 

  45. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ . The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol 2004; 57: 68–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S . Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006; 61: 940–944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hancox RJ, Sears MR, Taylor DR . Polymorphism of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma. Eur Respir J 1998; 11: 589–593.

    CAS  PubMed  Google Scholar 

  48. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004; 364: 1505–1512.

    Article  CAS  PubMed  Google Scholar 

  49. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI . Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax 2000; 55: 762–767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Weiss ST, Lake SL, Silverman ES, Silverman EK, Richter B, Drazen JM et al. Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses. Proc Am Thorac Soc 2004; 1: 364–367.

    Article  CAS  PubMed  Google Scholar 

  51. Kim WJ, Sheen SS, Kim TH, Huh JW, Lee JH, Kim EK et al. Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD. Respirology 2009; 14: 260–263.

    Article  PubMed  Google Scholar 

  52. Wilker EH, Alexeeff SE, Poon A, Litonjua AA, Sparrow D, Vokonas PS et al. Candidate genes for respiratory disease associated with markers of inflammation and endothelial dysfunction in elderly men. Atherosclerosis 2009; 206: 480–485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dautzenberg FM, Hauger RL . The CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol Sci 2002; 23: 71–77.

    Article  CAS  PubMed  Google Scholar 

  54. Barnes PJ . Histone deacetylase-2 and airway disease. Ther Adv Respir Dis 2009; 3: 235–243.

    Article  PubMed  Google Scholar 

  55. Barnes PJ . Inhaled corticosteroids in COPD: a controversy. Respiration 2010; 80: 89–95.

    Article  CAS  PubMed  Google Scholar 

  56. Barnes KC, Grant AV, Gao P . A review of the genetic epidemiology of resistance to parasitic disease and atopic asthma: common variants for common phenotypes? Curr Opin Allergy Clin Immunol 2005; 5: 379–385.

    Article  CAS  PubMed  Google Scholar 

  57. Miller RG . Simultaneous Statistical Inference. Springer Verlag: New York, 2010.

    Google Scholar 

Download references

Acknowledgements

We acknowledge the ALA-ACRC investigators and research teams who conducted the LOCCS and LODO trials. We would also like to acknowledge Stacey Gray for help with preparation of the manuscript. This work was supported by the National Institutes of Health (R01HL071394, R01HL074755, K23HL081245, R01HL092197, and U01HL065899) and the American Lung Association.

Author Contributions

E.B. Mougey conducted the analysis and interpretation, and drafted the manuscript for intellectual content; C. Chen developed the study design, statistics and association analysis; K.G. Tantisira contributed to the conception, design, analysis, interpretation and funding; K.V. Blake contributed to the conception, design, funding, trials and drafted the manuscript for intellectual content; S.P. Peters contributed to the conception, design and trials; R.A. Wise contributed to the conception, design and trials; S.T. Weiss contributed to the conception, design and funding; J.J.Lima (P.I.) contributed to the conception, design, analysis, interpretation, funding; drafted the manuscript for intellectual content, and is the guarantor.

Author information

Authors and Affiliations

  1. ALA-Asthma Clinical Research Center, Jacksonville, FL, USA

    E B Mougey, K V Blake, S P Peters, R A Wise & J J Lima

  2. Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, FL, USA

    E B Mougey, K V Blake & J J Lima

  3. Department of Biostatistics, Harvard School of Public Health, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    C Chen

  4. Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    K G Tantisira & S T Weiss

  5. Translational Science Institute, Wake Forest University Health Sciences Center, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC, USA

    S P Peters

  6. Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University and, Pulmonary & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    R A Wise

Authors
  1. E B Mougey
    View author publications

    Search author on:PubMed Google Scholar

  2. C Chen
    View author publications

    Search author on:PubMed Google Scholar

  3. K G Tantisira
    View author publications

    Search author on:PubMed Google Scholar

  4. K V Blake
    View author publications

    Search author on:PubMed Google Scholar

  5. S P Peters
    View author publications

    Search author on:PubMed Google Scholar

  6. R A Wise
    View author publications

    Search author on:PubMed Google Scholar

  7. S T Weiss
    View author publications

    Search author on:PubMed Google Scholar

  8. J J Lima
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to J J Lima.

Ethics declarations

Competing interests

Edward Mougey and John Lima received funding from Merck to characterize associations between transporter SNPs, and the pharmacokinetics and pharmacodynamics of montelukast. Stephen Peters received compensation as a consultant to the ALA-ACRC DCC. Robert Wise received compensation as a consultant to the following companies: Astra Zeneca, Boehringer-Ingelheim, GSK, Novartis, Sunovion, Centocor, Genentech, Medimmune, Intermune and Pfizerone. Dr Wise is also funded by the following companies: Boehringer-Ingelheim, GSK, Merck Forest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mougey, E., Chen, C., Tantisira, K. et al. Pharmacogenetics of asthma controller treatment. Pharmacogenomics J 13, 242–250 (2013). https://doi.org/10.1038/tpj.2012.5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/tpj.2012.5

Keywords

This article is cited by

Search

Advanced search

Quick links