The influence of the AA 16 beta 2-adrenoceptor polymorphism on systemic and airway responses in asthma

The impact of the polymorphic amino acids 16 and 27 of the beta 2-adrenoceptor (beta 2-AR) on the susceptibility to bronchodilator tolerance remains unclear since clinical studies thus far have shown discordant results. Tolerance towards the effects of inhaled beta 2-AR agonists generally is more easily shown for systemic parameters than for airway effects and can be substantial. This study evaluates whether differences exist between position 16 homozygous genotyped asthmatics, in tolerance development towards airway responses and the systemic effect hypokalemia.

Twenty patients were genotyped for amino acids 16 and 27 of the beta 2-AR gene. Time-effect curves for FEV1 and serum potassium concentration were constructed after s.c. administration of terbutaline after two-week treatment periods with either terbutaline inhalation or matching placebo in a double-blind, randomised and cross-over design. Statistical analysis was done by a repeated measures multivariate analysis on area under time-effect curve (AUC).

Pre-treatment with inhaled terbutaline did not influence the improvement in FEV1 in response to s.c. terbutaline and there were no significant differences between Arg-16 and Gly-16 individuals in this respect. Pre-treatment with inhaled terbutaline resulted in an overall increase of baseline plasma potassium before administration of s.c. terbutaline (3.78-3.95 mmol/L, p=0.034). However, this effect appeared to be solely confined to the Arg-16 homozygous individuals, leading to a statistically highly significant difference between the Arg-16 and Gly-16 subjects (p=0.005). However, there was no genotype related difference in the decrease in plasma potassium response to s.c. terbutaline relative to baseline.

In patients carrying the Arg-16 genotype the development of hypokalemia by s.c. terbutaline is attenuated after pre-treatment with inhaled terbutaline, be it on the basis of higher baseline values.