Effects of genetic polymorphism on ex vivo and in vivo function of beta(2)-adrenoceptors in asthmatic patients

Background: Genetic polymorphism determines agonist-induced down-regulation and desensitization of beta(2)-adrenoceptors. Objectives: The aim of the present study was to investigate the effects of genetic polymorphism on ex vivo (lymphocytes) and in vivo (bronchoprotectio n) function of beta(2)-adrenoceptors in asthmatic patients, having been was hed out of previous beta(2)-agonist exposure. Methods: Sixty patients with stable mild-to-moderate asthma were evaluated, with a post hoc analysis of genotype performed at end of study. Having wit hheld treatment with long-acting beta(2)-agonists for greater than or equal to 48 h and short-acting beta(2)-agonists for greater than or equal to 12 h, measurements of lymphocyte beta(2)-adrenoceptors were made for binding d ensity, binding affinity, basal cyclic adenosine monophosphate (cAMP), and maximal cAMP response to isoproterenol (Emax). In addition, in 48 of these patients who were methacholine responsive (PD20 < 1,000 mu g), the acute pr otective effect of formoterol as a 24-mu g single dose (at 1 h) was also ev aluated. Comparisons were made according to homozygous and heterozygous (He t) polymorphisms at codon 16 and codon 27. Results: There were no significant differences in age, FEV, percent predict ed, or inhaled corticosteroid dose, when comparing mean values for polymorp hisms at either codon 16 or codon 27, There were also no significant differ ences between polymorphisms for any of the measured lymphocyte beta(2)-adre noceptor parameters apart from basal cAMP between Glu-27 and Het-27. Mean v alues for Emax (after-before isoproterenol as pmol/10(6) cells) were as fol lows: Gly-16 (3.4), Arg-16 (3.5), Het-16 (4.0), Glu-27 (3.9), Gln-27 (3.5), and Het-27 (3.7), Polymorphism had no significant effect on formoterol pro tection as doubling dose shift in methacholine PD,, (geometric mean): Gly-1 6 (5.3), Arg-16 (5.4), Het-16 (4.6), Glu-27 (5.3), Gln-27 (5.3), Het-27 (4. 5). Conclusions: Our results show that genetic polymorphism at codon 16 or 27 d oes not influence stimulated coupling of lymphocyte beta(2)-adrenoceptors a nd similarly did not influence the degree of functional antagonism exhibite d by formoterol. Thus, a single dose of beta(2)-agonist when used on demand affords equal protection against bronchoprotection regardless of genetic p olymorphism.