Heterogeneity of therapeutic responses in asthma.

Asthma is a complex clinical syndrome with multiple genetic and environmental factors contributing to its phenotypic expression. This aetiological heterogeneity adds to the complexity when addressing variation in the response to anti-asthma treatment. Currently, there are three main lines of treatment available: (i) inhaled glucocorticoids which have multiple mechanisms of action; (ii) beta 2-agonists which are very effective bronchodilators and act predominantly on airway smooth muscle; and (iii) cysteinyl-leukotriene inhibitors. Analysis of the repeatability (r) of the treatment response, defined as the fraction of the total population variance which results from among-individual differences, shows values of r between 60-80% indicating that a substantial fraction of the variance of the treatment response could be genetic in nature. Among the sources of variability that could contribute to the observed heterogeneity in the response to treatment are the degree of underlying inflammation, such as in glucocorticoid resistance, and polymorphisms in the genes encoding the drug target, such as beta 2-adrenoceptor and 5-lipoxygenase.

[1]  S. Leal Genetics and Analysis of Quantitative Traits , 2001 .

[2]  E. Silverman,et al.  The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. , 2000, American journal of respiratory and critical care medicine.

[3]  A. Sousa,et al.  In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation. , 1999, The Journal of allergy and clinical immunology.

[4]  Nicholas Schork,et al.  Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment , 1999, Nature Genetics.

[5]  I. Hall,et al.  β2-Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy , 1999 .

[6]  I. Hall,et al.  Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta2-agonist therapy. , 1999, Clinical science.

[7]  I. Adcock,et al.  Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. , 1998, The Journal of clinical investigation.

[8]  G. Town,et al.  Asthma control during long term treatment with regular inhaled salbutamol and salmeterol , 1998, Thorax.

[9]  Britton,et al.  β2‐adrenoceptor polymorphisms are in linkage disequilibrium, but are not associated with asthma in an adult population , 1998, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[10]  R. Hancox,et al.  Polymorphism of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma. , 1998, The European respiratory journal.

[11]  R. Erickson,et al.  Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. , 1997, The Journal of clinical investigation.

[12]  G. Chrousos,et al.  Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor β , 1997, The Journal of experimental medicine.

[13]  P. Stephenson Statement concerning the second revision of the British guidelines on asthma management , 1997 .

[14]  E. Silverman,et al.  Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. , 1997, The Journal of clinical investigation.

[15]  Lane Sj Pathogenesis of steroid-resistant asthma. , 1997 .

[16]  S. Lane,et al.  Effects of prednisolone on bone turnover in patients with corticosteroid resistant asthma , 1996, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[17]  E. Israel,et al.  Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. , 1996, The New England journal of medicine.

[18]  T. Lee,et al.  Hypothalamic-pituitary-adrenal axis in corticosteroid-resistant bronchial asthma. , 1996, American journal of respiratory and critical care medicine.

[19]  I. Adcock,et al.  529 Increased c-fos synthesis in mononuclear cells from patients with corticosteroid resistent asthma , 1996 .

[20]  P. Barnes,et al.  Glucocorticoid resistance in asthma. , 1995, American journal of respiratory and critical care medicine.

[21]  I. Adcock,et al.  Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma , 1995, The Journal of experimental medicine.

[22]  I. Hall,et al.  Association of Glu 27 β2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects , 1995, The Lancet.

[23]  I. Adcock,et al.  Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. , 1995, Journal of immunology.

[24]  S. Green,et al.  Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. , 1995, The Journal of clinical investigation.

[25]  P. Enright,et al.  Spirometry in the Lung Health Study: II. Determinants of short-term intraindividual variability. , 1995, American journal of respiratory and critical care medicine.

[26]  R. Martin,et al.  Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma , 1995, The Journal of experimental medicine.

[27]  J. Arm,et al.  Chemical mutational analysis of the human glucocorticoid receptor cDNA in glucocorticoid-resistant bronchial asthma. , 1994, American journal of respiratory cell and molecular biology.

[28]  S. Szefler,et al.  Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. , 1994, The Journal of clinical investigation.

[29]  S. Liggett,et al.  Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. , 1993, American journal of respiratory cell and molecular biology.

[30]  Alfred O. Berg,et al.  Clinical Guidelines And Primary Care Guidelines For The Diagnosis And Management Of Asthma , 2012 .

[31]  E. Israel,et al.  Recovery of leukotriene E4 from the urine of patients with airway obstruction. , 1992, The American review of respiratory disease.

[32]  S. Szefler,et al.  Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. , 1991, The American review of respiratory disease.

[33]  C. Madden Regular inhaled beta-agonist treatment in bronchial asthma , 1991 .

[34]  T. Lee,et al.  Glucocorticoid receptor characteristics in monocytes of patients with corticosteroid-resistant bronchial asthma. , 1991, The American review of respiratory disease.

[35]  A. Buist,et al.  Spirometry in the Lung Health Study , 1991 .

[36]  S. Marney,et al.  Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans. Effect of indomethacin. , 1990, The American review of respiratory disease.

[37]  P. Piper Leukotrienes and the airways. , 1989, European journal of anaesthesiology.

[38]  C. Dollery,et al.  URINARY LEUKOTRIENE E4 AFTER ANTIGEN CHALLENGE AND IN ACUTE ASTHMA AND ALLERGIC RHINITIS , 1989, The Lancet.

[39]  C. M. Lessells,et al.  Unrepeatable repeatabilities: a common mistake , 1987 .

[40]  B. Samuelsson Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. , 1983, Science.

[41]  G. Crompton,et al.  Corticosteroid resistance in chronic asthma , 1981, British medical journal.

[42]  W. Jusko,et al.  Prednisolone disposition in steroid-dependent asthmatic children. , 1981, The Journal of allergy and clinical immunology.

[43]  F. Bochner,et al.  Prednisolone pharmacokinetics in asthmatic patients. , 1980, British journal of diseases of the chest.

[44]  F. C. Lowell,et al.  Steroid resistance in bronchial asthma. , 1968, Annals of internal medicine.

[45]  Cedric A. B. Smith,et al.  Introduction to Quantitative Genetics , 1960 .