title: Tachyphylaxis to beta2-agonists in Spanish asthmatic patients could be modulated by beta2-adrenoceptor gene polymorphisms.
abstract: BACKGROUND
  The study of determinants of asthma is a subject of much interest currently, especially the pharmacogenetic aspects of asthma management. Genetic polymorphisms affecting amino-acids at positions 16 and 27 within beta(2)-adrenoceptor (beta(2)AR) gene have been implicated in the asthma phenotypes and influence on the variability observed in response to use of bronchodilator agents used in the treatment of asthma. Whether these polymorphisms alter the bronchoprotection response to beta(2)-agonist treatment in Spanish asthmatic population is unknown. The aim of this study was to investigate whether genetic polymorphisms within beta(2)AR gene modulate the clinical outcomes of the individual response to beta(2)-agonist therapy and the development of desensitization in Spanish asthmatic patients.
  
  
  METHODS
  In a prospective, case-control study were included 80 asthmatic patients. Based on the standard criteria, patients were classified into two groups: patients with tachyphylaxis and good responders to beta(2)-agonist therapy. DNA samples were genotyped for the Arg(16)Gly and Glu(27)Gln alleles within the beta(2)AR gene as well as in 64 control samples from blood donors.
  
  
  RESULTS
  Arg(16) allele was slightly more frequent within the group with tachyphylaxis (P=0.039), whereas Gly(16) allele carriers were overrepresented within the group of good responders (59.7%, P=0.028). On the other hand, the allele frequency of Gln(27) and the proportion of Gln(27) carriers was higher within the group with tachyphylaxis (P=0.010 and 0.049, respectively) and Glu(27) allele carriers were overrepresented within the group of good responders (P=0.026). The Arg(16) and Gln(27) alleles were in strong linkage disequilibrium across this locus, resulting in the occurrence of disease haplotype.
  
  
  CONCLUSIONS
  The predisposition to develop tachyphylaxis in our population seems to be linked to the Arg(16) and Gln(27) alleles and to the Arg(16)/Gln(27) risk haplotype (positive association between the presence of the Arg(16) and Gln(27) alleles and tachyphylaxis). The Arg(16) allele is perhaps overrepresented due to the strong linkage disequilibrium between both polymorphisms. The presence of the Glu(27) allele seems to be a protective factor against tachyphylaxis in this cohort study.
authors.affiliation: Department of Paediatrics, Institute of Biology and Molecular Genetics, IBGM/CSIC, University of Valladolid School of Medicine, Valladolid, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Tellería
authors.forename: Alfredo
authors.initials: A
authors.lastname: Blanco-Quirós
authors.forename: Sandra
authors.initials: S
authors.lastname: Muntión
authors.forename: Jose
authors.initials: J
authors.lastname: Antonio Garrote
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arranz
authors.forename: Alicia
authors.initials: A
authors.lastname: Armentia
authors.forename: Ignacio
authors.initials: I
authors.lastname: Díez
authors.forename: Jesús
authors.initials: J
authors.lastname: Castro
mesh_terms: D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000188:drug therapy / Q000235:genetics*; D001985:Bronchial Provocation Tests; D016022:Case-Control Studies; D004334:Drug Administration Schedule; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D013618:Tachyphylaxis / Q000235:genetics*; D017211:Treatment Failure
chemical_list: D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2