Advertisement

Pharmacogenetics of Asthma

  • Anthony G. FenechEmail author
  • Ian Sayers
  • Michael A. Portelli
Chapter
Part of the Advances in Predictive, Preventive and Personalised Medicine book series (APPPM, volume 9)

Abstract

The study of pharmacogenetics has expanded from what were initially casual drug response observations present in families, to a fully-fledged science with direct therapeutic applications, within a timespan of less than 60 years. Within the field of asthma therapeutics, heterogeneity in patient response to therapeutic agents has been reported from various studies, and several genotype associations with specific therapeutic-response phenotypes have been established. There is however much to be accomplished. The future of asthma pharmacogenetics lies in consolidating and validating clinically important pharmacogenes which are relevant to currently available therapy, and to integrate itself into day to day drug management and the drug development process, in order to streamline the discovery of the potential pharmacogenetic relevance of new drugs. This chapter reviews the pharmacogenetics of current asthma therapies, and discusses challenges which need to be addressed in order to enable the optimisation and personalisation of patient management in a genotype-dependent manner.

Keywords

Pharmacogenetics Asthma Drug development Genotype-guided prescribing Predictive therapeutics 

References

  1. 1.
    GINA (Global Initiative for Asthma) (2014) Global strategy for asthma management and prevention. www.ginasthma.org
  2. 2.
    Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, Boulet LP, Brightling C, Chanez P, Dahlen SE, Djukanovic R, Frey U, Gaga M, Gibson P, Hamid Q, Jajour NN, Mauad T, Sorkness RL, Teague WG (2014) International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 43(2):343–373. doi:10.1183/09031936.00202013PubMedGoogle Scholar
  3. 3.
    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 Critical Car Med 174(10):1101–1109. doi:10.1164/rccm.200509-1405OCGoogle Scholar
  4. 4.
    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(3):334–339. doi:10.1165/ajrcmb/8.3.334PubMedGoogle Scholar
  5. 5.
    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(19):10483–10488PubMedCentralPubMedGoogle Scholar
  6. 6.
    Sayers I, Hall IP (2005) Pharmacogenetic approaches in the treatment of asthma. Curr Allergy Asthma Rep 5(2):101–108PubMedGoogle Scholar
  7. 7.
    Hall IP, Sayers I (2007) Pharmacogenetics and asthma: false hope or new dawn? Eur Respir J 29(6):1239–1245. doi:10.1183/09031936.00088206PubMedGoogle Scholar
  8. 8.
    Pascual RM, Bleecker ER (2010) Pharmacogenetics of asthma. Curr Opin Pharmacol 10(3):226–235. doi:10.1016/j.coph.2010.05.013PubMedGoogle Scholar
  9. 9.
    Tse SM, Tantisira K, Weiss ST (2011) The pharmacogenetics and pharmacogenomics of asthma therapy. Pharmacogenomics J 11(6):383–392. doi:10.1038/tpj.2011.46PubMedCentralPubMedGoogle Scholar
  10. 10.
    Sayers I, Hawley J, Stewart CE, Billington CK, Henry A, Leighton-Davies JR, Charlton SJ, Hall IP (2009) Pharmacogenetic characterization of indacaterol, a novel beta 2-adrenoceptor agonist. Br J Pharmacol 158(1):277–286. doi:10.1111/j.1476-5381.2009.00224.xPubMedCentralPubMedGoogle Scholar
  11. 11.
    Lee MY, Cheng SN, Chen SJ, Huang HL, Wang CC, Fan HC (2011) Polymorphisms of the beta2-adrenergic receptor correlated to nocturnal asthma and the response of terbutaline nebulizer. Pediatr Neonatol 52(1):18–23. doi:10.1016/j.pedneo.2010.12.011PubMedGoogle Scholar
  12. 12.
    Basu K, Palmer CN, Tavendale R, Lipworth BJ, Mukhopadhyay S (2009) Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. J Allergy Clin Immunol 124(6):1188–1194e1183. doi:10.1016/j.jaci.2009.07.043PubMedGoogle Scholar
  13. 13.
    Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M (2007) Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 370(9605):2118–2125. doi:10.1016/S0140-6736(07)61906-0PubMedGoogle Scholar
  14. 14.
    Slager RE, Hawkins GA, Ampleford EJ, Bowden A, Stevens LE, Morton MT, Tomkinson A, Wenzel SE, Longphre M, Bleecker ER, Meyers DA (2010) IL-4 receptor alpha polymorphisms are predictors of a pharmacogenetic response to a novel IL-4/IL-13 antagonist. J Allerg Clin Immunol 126(4):875–878. doi:10.1016/j.jaci.2010.08.001Google Scholar
  15. 15.
    Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, Ameredes BT, Castro M, Craig TJ, Denlinger L, Fahy JV, Jarjour N, Kazani S, Kim S, Kraft M, Lazarus SC, Lemanske RF, Jr, Markezich A, Martin RJ, Permaul P, Peters SP, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Walter MJ, Wasserman SI, Israel E (2009) National Heart L, Blood Instituteʼs Asthma Clinical Research N Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet 374(9703):1754–1764. doi:10.1016/S0140-6736(09)61492-6PubMedCentralPubMedGoogle Scholar
  16. 16.
    Panebra A, Wang WC, Malone MM, Pitter DR, Weiss ST, Hawkins GA, Liggett SB (2010) Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes. PloS One 5(7):e11819. doi:10.1371/journal.pone.0011819PubMedCentralPubMedGoogle Scholar
  17. 17.
    Thangapandian S, John S, Son M, Arulalapperumal V, Lee KW (2013) Development of predictive quantitative structure-activity relationship model and its application in the discovery of human leukotriene A4 hydrolase inhibitors. Future Med Chem 5(1):27–40. doi:10.4155/fmc.12.184PubMedGoogle Scholar
  18. 18.
    Litonjua AA, Lasky-Su J, Schneiter K, Tantisira KG, Lazarus R, Klanderman B, Lima JJ, Irvin CG, Peters SP, Hanrahan JP, Liggett SB, Hawkins GA, Meyers DA, Bleecker ER, Lange C, Weiss ST (2008) ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts. Am J Respir Crit Care Med 178(7):688–694. doi:10.1164/rccm.200709-1363OCPubMedCentralPubMedGoogle Scholar
  19. 19.
    Meurs H, McKay S, Maarsingh H, Hamer MA, Macic L, Molendijk N, Zaagsma J (2002) Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness. Br J Pharmacol 136(3):391–398. doi:10.1038/sj.bjp.0704725PubMedCentralPubMedGoogle Scholar
  20. 20.
    Maarsingh H, Zuidhof AB, Bos IS, van Duin M, Boucher JL, Zaagsma J, Meurs H (2008) Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation. Am J Respir Crit Care Med 178(6):565–573. doi:10.1164/rccm.200710-1588OCPubMedGoogle Scholar
  21. 21.
    Vonk JM, Postma DS, Maarsingh H, Bruinenberg M, Koppelman GH, Meurs H (2010) Arginase 1 and arginase 2 variations associate with asthma, asthma severity and beta2 agonist and steroid response. Pharmacogenet Genomics 20(3):179–186. doi:10.1097/FPC.0b013e328336c7fdPubMedGoogle Scholar
  22. 22.
    Duan QL, Gaume BR, Hawkins GA, Himes BE, Bleecker ER, Klanderman B, Irvin CG, Peters SP, Meyers DA, Hanrahan JP, Lima JJ, Litonjua AA, Tantisira KG, Liggett SB (2011) Regulatory haplotypes in ARG1 are associated with altered bronchodilator response. Am J Respir Crit Care Med 183(4):449–454. doi:10.1164/rccm.201005-0758OCPubMedCentralPubMedGoogle Scholar
  23. 23.
    Moore PE, Ryckman KK, Williams SM, Patel N, Summar ML, Sheller JR (2009) Genetic variants of GSNOR and ADRB2 influence response to albuterol in African-American children with severe asthma. Pediatr Pulmonol 44(7):649–654. doi:10.1002/ppul.21033PubMedGoogle Scholar
  24. 24.
    Gaston B, Reilly J, Drazen JM, Fackler J, Ramdev P, Arnelle D, Mullins ME, Sugarbaker DJ, Chee C, Singel DJ et al. (1993) Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways. Proc Natl Acad Sci USA 90(23):10957–10961PubMedCentralPubMedGoogle Scholar
  25. 25.
    Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS (2007) Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129(3):511–522. doi:10.1016/j.cell.2007.02.046PubMedGoogle Scholar
  26. 26.
    Choudhry S, Que LG, Yang Z, Liu L, Eng C, Kim SO, Kumar G, Thyne S, Chapela R, Rodriguez-Santana JR, Rodriguez-Cintron W, Avila PC, Stamler JS, Burchard EG (2010) GSNO reductase and beta2-adrenergic receptor gene-gene interaction: bronchodilator responsiveness to albuterol. Pharmacogenet Genomics 20(6):351–358. doi:10.1097/FPC.0b013e328337f992PubMedCentralPubMedGoogle Scholar
  27. 27.
    Himes BE, Jiang X, Wagner P, Hu R, Wang Q, Klanderman B, Whitaker RM, Duan Q, Lasky-Su J, Nikolos C, Jester W, Johnson M, Panettieri RA, Jr, Tantisira KG, Weiss ST, Lu Q (2014) RNA-Seq transcriptome profiling identifies CRISPLD2 as a glucocorticoid responsive gene that modulates cytokine function in airway smooth muscle cells. PloS One 9(6):e99625. doi:10.1371/journal.pone.0099625PubMedCentralPubMedGoogle Scholar
  28. 28.
    Kellaway CH, Trethewie ER (1940) The liberation of a slow-reacting smooth muscle-stimulating substance in anaphylaxis. Exp Physiol 30(2):121–145Google Scholar
  29. 29.
    Brocklehurst WE (1960) The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock. J Physiol 151:416–435PubMedCentralPubMedGoogle Scholar
  30. 30.
    Duroudier NP, Tulah AS, Sayers I (2009) Leukotriene pathway genetics and pharmacogenetics in allergy. Allergy 64(6):823–839. doi:10.1111/j.1398-9995.2009.02015.xPubMedGoogle Scholar
  31. 31.
    Via M, De Giacomo A, Corvol H, Eng C, Seibold MA, Gillett C, Galanter J, Sen S, Tcheurekdjian H, Chapela R, Rodriguez-Santana JR, Rodriguez-Cintron W, Thyne S, Avila PC, Choudhry S, Gonzalez Burchard E, Genetics of Asthma in Latino Americans S (2010) The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos. Clin Exp Allergy: J Br Soc Allergy Clin Immunol 40(4):582–589. doi:10.1111/j.1365-2222.2009.03438.xGoogle Scholar
  32. 32.
    Tulah AS, Parker SG, Moffatt MF, Wardlaw AJ, Connolly MJ, Sayers I (2011) The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers. BMC Med Genet 12:173. doi:10.1186/1471-2350-12-173PubMedCentralPubMedGoogle Scholar
  33. 33.
    Holloway JW, Barton SJ, Holgate ST, Rose-Zerilli MJ, Sayers I (2008) The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility. Allergy 63(8):1046–1053. doi:10.1111/j.1398-9995.2008.01667.xPubMedGoogle Scholar
  34. 34.
    Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J (1999) Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 22(2):168–170. doi:10.1038/9680PubMedGoogle Scholar
  35. 35.
    Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H, Wang J, Sylvester J, Holbrook J, Wise R, Weiss ST, Barnes K (2006) Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med 173(4):379–385. doi:10.1164/rccm.200509-1412OCPubMedCentralPubMedGoogle Scholar
  36. 36.
    Telleria JJ, Blanco-Quiros A, Varillas D, Armentia A, Fernandez-Carvajal I, Jesus Alonso M, Diez I (2008) ALOX5 promoter genotype and response to montelukast in moderate persistent asthma. Respir Med 102(6):857–861. doi:10.1016/j.rmed.2008.01.011PubMedGoogle Scholar
  37. 37.
    Klotsman M, York TP, Pillai SG, Vargas-Irwin C, Sharma SS, van den Oord EJ, Anderson WH (2007) Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics 17(3):189–196. doi:10.1097/FPC.0b013e3280120043PubMedGoogle Scholar
  38. 38.
    Tantisira KG, Lima J, Sylvia J, Klanderman B, Weiss ST (2009) 5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci. Pharmacogenet Genomics 19(3):244–247. doi:10.1097/FPC.0b013e328326e0b1PubMedCentralPubMedGoogle Scholar
  39. 39.
    Asano K, Shiomi T, Hasegawa N, Nakamura H, Kudo H, Matsuzaki T, Hakuno H, Fukunaga K, Suzuki Y, Kanazawa M, Yamaguchi K (2002) Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics 12(7):565–570PubMedGoogle Scholar
  40. 40.
    Tcheurekdjian H, Via M, De Giacomo A, Corvol H, Eng C, Thyne S, Chapela R, Rodriguez-Cintron W, Rodriguez-Santana JR, Avila PC, Burchard EG, Genetics of Asthma in Latino Americans S (2010) ALOX5AP and LTA4H polymorphisms modify augmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos. J Allergy Clin Immunol 126(4):853–858. doi:10.1016/j.jaci.2010.06.048Google Scholar
  41. 41.
    Kim SH, Ye YM, Hur GY, Lee SK, Sampson AP, Lee HY, Park HS (2007) CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients. Pharmacogenomics 8(9):1143–1150. doi:10.2217/14622416.8.9.1143PubMedGoogle Scholar
  42. 42.
    Brochu-Bourque A, Veronneau S, Rola-Pleszczynski M, Stankova J (2011) Differential signaling defects associated with the M201V polymorphism in the cysteinyl leukotriene type 2 receptor. J Pharmacol Exp Ther 336(2):431–439. doi:10.1124/jpet.110.172411PubMedGoogle Scholar
  43. 43.
    Sayers I, Sampson AP, Ye S, Holgate ST (2003) Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene. Eur J Hum Genet 11(8):619–622. doi:10.1038/sj.ejhg.5201015PubMedGoogle Scholar
  44. 44.
    Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ (2009) Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics 19(2):129–138. doi:10.1097/FPC.0b013e32831bd98cPubMedCentralPubMedGoogle Scholar
  45. 45.
    Reid JJ (2001) ABT-761 (Abbott). Curr Opin Investig Drugs 2(1):68–71PubMedGoogle Scholar
  46. 46.
    Mougey E, Lang JE, Allayee H, Teague WG, Dozor AJ, Wise RA, Lima JJ (2013) ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma. Clin Exp Allergy: J Br Soc Allergy Clin Immunol 43(5):512–520. doi:10.1111/cea.12076Google Scholar
  47. 47.
    Nwokoro C, Pandya H, Turner S, Eldridge S, Griffiths CJ, Vulliamy T, Price D, Sanak M, Holloway JW, Brugha R, Koh L, Dickson I, Rutterford C, Grigg J (2014) Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial. Lancet Respir Med 2(10):796–803. doi:10.1016/S2213-2600(14)70186-9PubMedCentralPubMedGoogle Scholar
  48. 48.
    Choi JH, Park HS, Oh HB, Lee JH, Suh YJ, Park CS, Shin HD (2004) Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. Hum Genet 114(4):337–344. doi:10.1007/s00439-004-1082-1PubMedGoogle Scholar
  49. 49.
    Thompson MD, Capra V, Takasaki J, Maresca G, Rovati GE, Slutsky AS, Lilly C, Zamel N, McIntyre Burnham W, Cole DE, Siminovitch KA (2007) A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate. Pharmacogenet Genomics 17(7):539–549. doi:10.1097/FPC.0b013e328012d0bfPubMedGoogle Scholar
  50. 50.
    Park JS, Chang HS, Park CS, Lee JH, Lee YM, Choi JH, Park HS, Kim LH, Park BL, Choi YH, Shin HD (2005) Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics. Pharmacogenet Genomics 15(7):483–492PubMedGoogle Scholar
  51. 51.
    Thompson MD, Storm vanʼs Gravesande K, Galczenski H, Burnham WM, Siminovitch KA, Zamel N, Slutsky A, Drazen JM, George SR, Evans JF, OʼDowd BF (2003) A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha. Pharmacogenetics 13(10):641–649. doi:10.1097/01.fpc.0000054127.14659.42PubMedGoogle Scholar
  52. 52.
    Pillai SG, Cousens DJ, Barnes AA, Buckley PT, Chiano MN, Hosking LK, Cameron LA, Fling ME, Foley JJ, Green A, Sarau HM, Schmidt DB, Sprankle CS, Blumenthal MN, Vestbo J, Kennedy-Wilson K, Wixted WE, Wagner MJ, Anderson WH, Ignar DM, Investigators of the GN (2004) A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma. Pharmacogenetics 14(9):627–633Google Scholar
  53. 53.
    Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E (2010) The human glucocorticoid receptor: molecular basis of biologic function. Steroids 75(1):1–12. doi:10.1016/j.steroids.2009.09.002PubMedCentralPubMedGoogle Scholar
  54. 54.
    Strehl C, Gaber T, Lowenberg M, Hommes DW, Verhaar AP, Schellmann S, Hahne M, Fangradt M, Wagegg M, Hoff P, Scheffold A, Spies CM, Burmester GR, Buttgereit F (2011) Origin and functional activity of the membrane-bound glucocorticoid receptor. Arthritis Rheum 63(12):3779–3788. doi:10.1002/art.30637PubMedGoogle Scholar
  55. 55.
    Kam JC, Szefler SJ, Surs W, Sher ER, Leung DY (1993) Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 151(7):3460–3466PubMedGoogle Scholar
  56. 56.
    Spahn JD, Szefler SJ, Surs W, Doherty DE, Nimmagadda SR, Leung DY (1996) A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity. J Immunol 157(6):2654–2659PubMedGoogle Scholar
  57. 57.
    Tliba O, Damera G, Banerjee A, Gu S, Baidouri H, Keslacy S, Amrani Y (2008) Cytokines induce an early steroid resistance in airway smooth muscle cells: novel role of interferon regulatory factor-1. Am J Respir Cell Mol Biol 38(4):463–472. doi:10.1165/rcmb.2007-0226OCPubMedCentralPubMedGoogle Scholar
  58. 58.
    Zijlstra GJ, Ten Hacken NH, Hoffmann RF, van Oosterhout AJ, Heijink IH (2012) Interleukin-17 A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur Respir J 39(2):439–445. doi:10.1183/09031936.00017911Google Scholar
  59. 59.
    Adcock IM, Barnes PJ (2008) Molecular mechanisms of corticosteroid resistance. Chest 134(2):394–401. doi:10.1378/chest.08-0440PubMedGoogle Scholar
  60. 60.
    Dejager L, Vandevyver S, Petta I, Libert C (2014) Dominance of the strongest: inflammatory cytokines versus glucocorticoids. Cytokine Growth Factor Rev 25(1):21–33. doi:10.1016/j.cytogfr.2013.12.006PubMedGoogle Scholar
  61. 61.
    Panek M, Pietras T, Antczak A, Gorski P, Kuna P, Szemraj J (2012) The role of functional single nucleotide polymorphisms of the human glucocorticoid receptor gene NR3C1 in Polish patients with bronchial asthma. Mol Biol Rep 39(4):4749–4757. doi:10.1007/s11033-011-1267-3PubMedCentralPubMedGoogle Scholar
  62. 62.
    Panek M, Pietras T, Fabijan A, Milanowski M, Wieteska L, Gorski P, Kuna P, Szemraj J (2013) Effect of glucocorticoid receptor gene polymorphisms on asthma phenotypes. Exp Ther Med 5(2):572–580. doi:10.3892/etm.2012.809PubMedCentralPubMedGoogle Scholar
  63. 63.
    Souza MC, Martins CS, Silva-Junior IM, Chriguer RS, Bueno AC, Antonini SR, Silva WA Jr, Zago MA, Moreira AC, Castro M (2014) NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association. Arq Bras Endocrinol Metabol 58(1):53–61PubMedGoogle Scholar
  64. 64.
    Russcher H, Dalm VA, de Jong FH, Brinkmann AO, Hofland LJ, Lamberts SW, Koper JW (2007) Associations between promoter usage and alternative splicing of the glucocorticoid receptor gene. J Mol Endocrinol 38(1–2):91–98. doi:10.1677/jme.1.02117PubMedGoogle Scholar
  65. 65.
    Ikeda Y, Suehiro T, Tsuzura S, Shiinoki T, Kaneda T, Kumon Y, Hashimoto K (2001) A polymorphism in the promoter region of the glucocorticoid receptor gene is associated with its transcriptional activity. Endocr J 48(6):723–726PubMedGoogle Scholar
  66. 66.
    Pietras T, Panek M, Tworek D, Oszajca K, Wujcik R, Gorski P, Kuna P, Szemraj J (2011) The Bcl I single nucleotide polymorphism of the human glucocorticoid receptor gene h-GR/NR3C1 promoter in patients with bronchial asthma: pilot study. Mol Biol Rep 38(6):3953–3958. doi:10.1007/s11033-010-0512-5PubMedCentralPubMedGoogle Scholar
  67. 67.
    Turner JD, Alt SR, Cao L, Vernocchi S, Trifonova S, Battello N, Muller CP (2010) Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. Biochem Pharmacol 80(12):1860–1868. doi:10.1016/j.bcp.2010.06.037PubMedGoogle Scholar
  68. 68.
    Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM (1985) Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318(6047):635–641PubMedGoogle Scholar
  69. 69.
    Encio IJ, Detera-Wadleigh SD (1991) The genomic structure of the human glucocorticoid receptor. J Biol Chem 266(11):7182–7188PubMedGoogle Scholar
  70. 70.
    Kino T, Su YA, Chrousos GP (2009) Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology. Cell Mol Life Sci 66(21):3435–3448. doi:10.1007/s00018-009-0098-zPubMedCentralPubMedGoogle Scholar
  71. 71.
    Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP (1991) Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest 87(2):680–686. doi:10.1172/JCI115046PubMedCentralPubMedGoogle Scholar
  72. 72.
    Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD (1993) A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest 91(5):1918–1925. doi:10.1172/JCI116410PubMedCentralPubMedGoogle Scholar
  73. 73.
    Niu N, Manickam V, Kalari KR, Moon I, Pelleymounter LL, Eckloff BW, Wieben ED, Schaid DJ, Wang L (2009) Human glucocorticoid receptor alpha gene (NR3C1) pharmacogenomics: gene resequencing and functional genomics. J Clin Endocrinol Metab 94(8):3072–3084. doi:10.1210/jc.2008-2109PubMedCentralPubMedGoogle Scholar
  74. 74.
    Tsartsali L, Papadopoulos M, Lagona E, Papadimitriou A, Kanaka-Gantenbein C, Louizou E, Kastania A, Priftis KN, Chrousos G (2012) Association of hypothalamic-pituitary-adrenal axis-related polymorphisms with stress in asthmatic children on inhaled corticosteroids. Neuroimmunomodulation 19(2):88–95. doi:10.1159/000329592PubMedGoogle Scholar
  75. 75.
    Cuzzoni E, De Iudicibus S, Bartoli F, Ventura A, Decorti G (2012) Association between BclI polymorphism in the NR3C1 gene and in vitro individual variations in lymphocyte responses to methylprednisolone. Br J Clin Pharmacol 73(4):651–655. doi:10.1111/j.1365-2125.2011.04130.xPubMedCentralPubMedGoogle Scholar
  76. 76.
    Panek M, Pietras T, Antczak A, Fabijan A, Przemecka M, Gorski P, Kuna P, Szemraj J (2012) The N363S and I559N single nucleotide polymorphisms of the h-GR/NR3C1 gene in patients with bronchial asthma. Int J Mol Med 30(1):142–150. doi:10.3892/ijmm.2012.956PubMedGoogle Scholar
  77. 77.
    Stevens A, Ray DW, Zeggini E, John S, Richards HL, Griffiths CE, Donn R (2004) Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype. J Clin Endocrinol Metab 8(2):892–897Google Scholar
  78. 78.
    Tantisira KG, Hwang ES, Raby BA, Silverman ES, Lake SL, Richter BG, Peng SL, Drazen JM, Glimcher LH, Weiss ST (2004) TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci USA 101(52):18099–18104. doi:10.1073/pnas.0408532102PubMedCentralPubMedGoogle Scholar
  79. 79.
    Lopert A, Rijavec M, Zavbi M, Korosec P, Flezar M (2013) Asthma treatment outcome in adults is associated with rs9910408 in TBX21 gene. Sci Rep 3:2915. doi:10.1038/srep02915PubMedCentralPubMedGoogle Scholar
  80. 80.
    Sakaeda T, Nakamura T, Okumura K (2002) MDR1 genotype-related pharmacokinetics and pharmacodynamics. Biol Pharm Bull 25(11):1391–1400PubMedGoogle Scholar
  81. 81.
    Siegsmund M, Brinkmann U, Schaffeler E, Weirich G, Schwab M, Eichelbaum M, Fritz P, Burk O, Decker J, Alken P, Rothenpieler U, Kerb R, Hoffmeyer S, Brauch H (2002) Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol 13(7):1847–1854PubMedGoogle Scholar
  82. 82.
    Ye YM, Lee HY, Kim SH, Jee YK, Lee SK, Lee SH, Park HS (2009) Pharmacogenetic study of the effects of NK2R G231E G > A and TBX21 H33Q C > G polymorphisms on asthma control with inhaled corticosteroid treatment. J Clin Pharm Ther 34(6):693–701. doi:10.1111/j.1365-2710.2009.01054.xPubMedGoogle Scholar
  83. 83.
    Hawkins GA, Lazarus R, Smith RS, Tantisira KG, Meyers DA, Peters SP, Weiss ST, Bleecker ER (2009) The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. J Allergy Clin Immunol 123(6):1376–1383, e1377. doi:10.1016/j.jaci.2009.01.049PubMedCentralPubMedGoogle Scholar
  84. 84.
    Jin Y, Hu D, Peterson EL, Eng C, Levin AM, Wells K, Beckman K, Kumar R, Seibold MA, Karungi G, Zoratti A, Gaggin J, Campbell J, Galanter J, Chapela R, Rodriguez-Santana JR, Watson HG, Meade K, Lenoir M, Rodriguez-Cintron W, Avila PC, Lanfear DE, Burchard EG, Williams LK (2010) Dual-specificity phosphatase 1 as a pharmacogenetic modifier of inhaled steroid response among asthmatic patients. J Allergy Clin Immunol 126(3):618–625 e611–612. doi:10.1016/j.jaci.2010.06.007PubMedCentralPubMedGoogle Scholar
  85. 85.
    Tantisira KG, Silverman ES, Mariani TJ, Xu J, Richter BG, Klanderman BJ, Litonjua AA, Lazarus R, Rosenwasser LJ, Fuhlbrigge AL, Weiss ST (2007) FCER2: a pharmacogenetic basis for severe exacerbations in children with asthma. J Allergy Clin Immunol 120(6):1285–1291. doi:10.1016/j.jaci.2007.09.005PubMedGoogle Scholar
  86. 86.
    Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, Lange C, Lazarus R, Sylvia J, Klanderman B, Duan QL, Qiu W, Hirota T, Martinez FD, Mauger D, Sorkness C, Szefler S, Lazarus SC, Lemanske RF Jr, Peters SP, Lima JJ, Nakamura Y, Tamari M, Weiss ST (2011) Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. New Engl J Med 365(13):1173–1183. doi:10.1056/NEJMoa0911353PubMedCentralPubMedGoogle Scholar
  87. 87.
    Huizenga NA, Koper JW, De Lange P, Pols HA, Stolk RP, Burger H, Grobbee DE, Brinkmann AO, De Jong FH, Lamberts SW (1998) A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 83(1):144–151. doi:10.1210/jcem.83.1.4490PubMedGoogle Scholar
  88. 88.
    Rosmond R, Bouchard C, Bjorntorp P (2001) Tsp509I polymorphism in exon 2 of the glucocorticoid receptor gene in relation to obesity and cortisol secretion: cohort study. BMJ 322(7287):652–653PubMedCentralPubMedGoogle Scholar
  89. 89.
    Syed AA, Irving JA, Redfern CP, Hall AG, Unwin NC, White M, Bhopal RS, Alberti KG, Weaver JU (2004) Low prevalence of the N363S polymorphism of the glucocorticoid receptor in South Asians living in the United Kingdom. J Clin Endocrinol Metab 89(1):232–235. doi:10.1210/jc.2003-030995PubMedGoogle Scholar
  90. 90.
    Koyano S, Saito Y, Sai K, Kurose K, Ozawa S, Nakajima T, Matsumoto K, Saito H, Shirao K, Yoshida T, Minami H, Ohtsu A, Saijo N, Sawada J (2005) Novel genetic polymorphisms in the NR3C1 (glucocorticoid receptor) gene in a Japanese population. Drug Metab Pharmacokinet 20(1):79–84PubMedGoogle Scholar
  91. 91.
    Duan ZX, Gu W, Du DY, Hu P, Jiang DP, Zhu PF, Wang ZG, Jiang JX (2009) Distributions of glucocorticoid receptor gene polymorphisms in a Chinese Han population and associations with outcome after major trauma. Injury 40(5):479–483. doi:10.1016/j.injury.2008.09.025PubMedGoogle Scholar
  92. 92.
    Goecke A, Guerrero J (2006) Glucocorticoid receptor beta in acute and chronic inflammatory conditions: clinical implications. Immunobiology 211(1–2):85–96. doi:10.1016/j.imbio.2005.11.002PubMedGoogle Scholar
  93. 93.
    Bamberger CM, Bamberger AM, de Castro M, Chrousos GP (1995) Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 95(6):2435–2441. doi:10.1172/JCI117943PubMedCentralPubMedGoogle Scholar
  94. 94.
    Pujols L, Mullol J, Roca-Ferrer J, Torrego A, Xaubet A, Cidlowski JA, Picado C (2002) Expression of glucocorticoid receptor alpha- and beta-isoforms in human cells and tissues. Am J Physiol Cell Physiol 283(4):C1324–1331. doi:10.1152/ajpcell.00363.2001PubMedGoogle Scholar
  95. 95.
    Lewis-Tuffin LJ, Cidlowski JA (2006) The physiology of human glucocorticoid receptor beta (hGRbeta) and glucocorticoid resistance. Ann N Y Acad Sci 1069:1–9. doi:10.1196/annals.1351.001PubMedGoogle Scholar
  96. 96.
    Kadmiel M, Cidlowski JA (2013) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci 34(9):518–530. doi:10.1016/j.tips.2013.07.003PubMedCentralPubMedGoogle Scholar
  97. 97.
    Vazquez-Tello A, Halwani R, Hamid Q, Al-Muhsen S (2013) Glucocorticoid receptor-beta up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells. J Clin Immunol 33(2):466–478. doi:10.1007/s10875-012-9828-3PubMedGoogle Scholar
  98. 98.
    Kamdem LK, Hamilton L, Cheng C, Liu W, Yang W, Johnson JA, Pui CH, Relling MV (2008) Genetic predictors of glucocorticoid-induced hypertension in children with acute lymphoblastic leukemia. Pharmacogenet genomics 18(6):507–514. doi:10.1097/FPC.0b013e3282fc5801PubMedGoogle Scholar
  99. 99.
    Nave R, McCracken N (2008) Metabolism of ciclesonide in the upper and lower airways: review of available data. J Asthma Allergy 1:11–18PubMedCentralPubMedGoogle Scholar
  100. 100.
    Wu MH, Chen P, Wu X, Liu W, Strom S, Das S, Cook EH Jr, Rosner GL, Dolan ME (2004) Determination and analysis of single nucleotide polymorphisms and haplotype structure of the human carboxylesterase 2 gene. Pharmacogenetics 14(9):595–605PubMedGoogle Scholar
  101. 101.
    Charasson V, Bellott R, Meynard D, Longy M, Gorry P, Robert J (2004) Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN-38. Clin Pharmacol Ther 76(6):528–535. doi:10.1016/j.clpt.2004.08.007PubMedGoogle Scholar
  102. 102.
    Crowe A, Tan AM (2012) Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol 260(3):294–302. doi:10.1016/j.taap.2012.03.008PubMedGoogle Scholar
  103. 103.
    Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH, Ackerman K, Haley K, Galle PR, Szabo SJ, Drazen JM, De Sanctis GT, Glimcher LH (2002) Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295(5553):336–338. doi:10.1126/science.1065544PubMedGoogle Scholar
  104. 104.
    Park HW, Dahlin A, Tse S, Duan QL, Schuemann B, Martinez FD, Peters SP, Szefler SJ, Lima JJ, Kubo M, Tamari M, Tantisira KG (2014) Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids. J Allergy Clin Immunol 133(3):664–669.e5. doi:10.1016/j.jaci.2013.12.1042PubMedCentralPubMedGoogle Scholar
  105. 105.
    Tautermann CS, Kiechle T, Seeliger D, Diehl S, Wex E, Banholzer R, Gantner F, Pieper MP, Casarosa P (2013) Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. J Med Chem 56(21):8746–8756. doi:10.1021/jm401219yPubMedGoogle Scholar
  106. 106.
    Fenech AG, Ebejer MJ, Felice AE, Ellul-Micallef R, Hall IP (2001) Mutation screening of the muscarinic M(2) and M(3) receptor genes in normal and asthmatic subjects. Br J Pharmacol 133(1):43–48. doi:10.1038/sj.bjp.0704039PubMedCentralPubMedGoogle Scholar
  107. 107.
    Szczepankiewicz A, Breborowicz A, Sobkowiak P, Kramer L, Popiel A (2009) Association of A/T polymorphism of the CHRM2 gene with bronchodilator response to ipratropium bromide in asthmatic children. Pneumonol Alergol Pol 77(1):5–10PubMedGoogle Scholar
  108. 108.
    Fenech AG, Billington CK, Swan C, Richards S, Hunter T, Ebejer MJ, Felice AE, Ellul-Micallef R, Hall IP (2004) Novel polymorphisms influencing transcription of the human CHRM2 gene in airway smooth muscle. Am J Respir Cell Mol Biol 30(5):678–686. doi:10.1165/rcmb.2003-0011OCPubMedGoogle Scholar
  109. 109.
    Donfack J, Kogut P, Forsythe S, Solway J, Ober C (2003) Sequence variation in the promoter region of the cholinergic receptor muscarinic 3 gene and asthma and atopy. J Allergy Clin Immunol 111(3):527–532PubMedGoogle Scholar
  110. 110.
    Maeda Y, Hizawa N, Jinushi E, Honda A, Takahashi D, Fukui Y, Konno S, Shimizu T, Shimizu H, Yamaguchi E (2006) Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma in Japanese subjects. Am J Respir Crit Care Med 174(10):1119–1124PubMedGoogle Scholar
  111. 111.
    Yamamoto T, Yamashita N, Kuwabara M, Nakano J, Sugimoto H, Akiyama K, Hirai K, Ishii A, Uehara Y, Ohta K (2002) Mutation screening of the muscarinic m2 and m3 receptor genes in asthmatics, outgrow subjects, and normal controls. Ann Genet 45(3):109–113PubMedGoogle Scholar
  112. 112.
    Lipworth BJ, Basu K, Donald HP, Tavendale R, Macgregor DF, Ogston SA, Palmer CN, Mukhopadhyay S (2013) Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond) 124(8):521–528. doi:10.1042/CS20120528Google Scholar
  113. 113.
    Ortega VE, Meyers DA (2014) Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. J Allergy Clin Immunol 133(1):16–26. doi:10.1016/j.jaci.2013.10.040PubMedCentralPubMedGoogle Scholar
  114. 114.
    Carter-Pokras OD, Gergen PJ (1993) Reported asthma among Puerto Rican, Mexican-American, and Cuban children, 1982 through 1984. Am J Public Health 83(4):580–582PubMedCentralPubMedGoogle Scholar
  115. 115.
    Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, Kraft M, Kunselman SJ, Lazarus SC, Lemanske RF Jr, Liggett SB, Martin RJ, Mitra N, Peters SP, Silverman E, Sorkness CA, Szefler SJ, Wechsler ME, Weiss ST, Drazen JM, National Heart L, Blood Instituteʼs Asthma Clinical Research N (2004) Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 364(9444):1505–1512. doi:10.1016/S0140-6736(04)17273-5Google Scholar
  116. 116.
    Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491(7422):56–65. doi:10.1038/nature11632Google Scholar
  117. 117.
    Shriner D (2013) Overview of admixture mapping. Curr Protoc Hum Genet Chapter 1:Unit 1.23. doi:10.1002/0471142905.hg0123s76Google Scholar
  118. 118.
    Winkler CA, Nelson GW, Smith MW (2010) Admixture mapping comes of age. Annu Rev Genomics Hum Genet 11:65–89. doi:10.1146/annurev-genom-082509-141523PubMedGoogle Scholar
  119. 119.
    Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. New Engl J Med 360(10):973–984. doi:10.1056/NEJMoa0808991PubMedCentralPubMedGoogle Scholar
  120. 120.
    Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG (2011) Lebrikizumab treatment in adults with asthma. New Engl J Med 365(12):1088–1098. doi:10.1056/NEJMoa1106469PubMedGoogle Scholar
  121. 121.
    Parulekar AD, Atik MA, Hanania NA (2014) Periostin, a novel biomarker of TH2-driven asthma. Curr Opin Pulm Med 20(1):60–65. doi:10.1097/MCP.0000000000000005PubMedGoogle Scholar
  122. 122.
    Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, Williams C, Hui J, Beilby J, Warrington NM, James A, Palmer LJ, Koppelman GH, Heinzmann A, Krueger M, Boezen HM, Wheatley A, Altmuller J, Shin HD, Uh ST, Cheong HS, Jonsdottir B, Gislason D, Park CS, Rasmussen LM, Porsbjerg C, Hansen JW, Backer V, Werge T, Janson C, Jonsson UB, Ng MC, Chan J, So WY, Ma R, Shah SH, Granger CB, Quyyumi AA, Levey AI, Vaccarino V, Reilly MP, Rader DJ, Williams MJ, van Rij AM, Jones GT, Trabetti E, Malerba G, Pignatti PF, Boner A, Pescollderungg L, Girelli D, Olivieri O, Martinelli N, Ludviksson BR, Ludviksdottir D, Eyjolfsson GI, Arnar D, Thorgeirsson G, Deichmann K, Thompson PJ, Wjst M, Hall IP, Postma DS, Gislason T, Gulcher J, Kong A, Jonsdottir I, Thorsteinsdottir U, Stefansson K (2009) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41(3):342–347. doi:10.1038/ng.323PubMedGoogle Scholar
  123. 123.
    Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO (2010) A large-scale, consortium-based genomewide association study of asthma. New Engl J Med 363(13):1211–1221. doi:10.1056/NEJMoa0906312PubMedCentralPubMedGoogle Scholar
  124. 124.
    Barnes KC (2010) Ancestry, ancestry-informative markers, asthma, and the quest for personalized medicine. J Allergy Clin Immunol 126(6):1139–1140. doi:10.1016/j.jaci.2010.10.032PubMedGoogle Scholar
  125. 125.
    Marandi Y, Farahi N, Hashjin GS (2013) Asthma: beyond corticosteroid treatment. Arch Med Sci 9(3):521–526. doi:10.5114/aoms.2013.33179PubMedCentralPubMedGoogle Scholar
  126. 126.
    Barnes PJ (2012) New drugs for asthma. Semin Respir Crit Care Med 33(6):685–694. doi:10.1055/s-0032-1326965PubMedGoogle Scholar
  127. 127.
    Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, She D, Kell C, May RD, Geba GP, Molfino NA (2013) A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 41(2):330–338. doi:10.1183/09031936.00223411PubMedCentralPubMedGoogle Scholar
  128. 128.
    Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G (2013) Dupilumab in persistent asthma with elevated eosinophil levels. New Engl J Med 368(26):2455–2466. doi:10.1056/NEJMoa1304048PubMedGoogle Scholar
  129. 129.
    Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M (2007) Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370(9596):1422–1431. doi:10.1016/s0140-6736(07)61600-6PubMedGoogle Scholar
  130. 130.
    Parker JM, Oh CK, LaForce C, Miller SD, Pearlman DS, Le C, Robbie GJ, White WI, White B, Molfino NA, Group M-CT (2011) Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm Med 11:14. doi:10.1186/1471-2466-11-14Google Scholar
  131. 131.
    Holgate ST, Noonan M, Chanez P, Busse W, Dupont L, Pavord I, Hakulinen A, Paolozzi L, Wajdula J, Zang C, Nelson H, Raible D (2011) Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J 37(6):1352–1359. doi:10.1183/09031936.00063510Google Scholar
  132. 132.
    Risma KA, Wang N, Andrews RP, Cunningham CM, Ericksen MB, Bernstein JA, Chakraborty R, Hershey GK (2002) V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function. J Immunol 169(3):1604–1610PubMedGoogle Scholar
  133. 133.
    Vogel F (1959) Moderne problem der humangenetik. Ergeb Inn Med Kinderheilkd 12:52–125Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Anthony G. Fenech
    • 1
    Email author
  • Ian Sayers
    • 2
  • Michael A. Portelli
    • 2
  1. 1.Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine and SurgeryUniversity of MaltaMsidaMalta
  2. 2.Division of Respiratory MedicineUniversity of Nottingham, Queen’s Medical CentreNottinghamUK

Personalised recommendations