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Abstract
Genetic variation in the structure of the β^sub 2^-adrenoceptor (ADRB2) is a potentially important source of variability in the response to β^sub 2^-agonist drugs. The relevant polymorphisms are common, with allele frequencies as high as 50% in some cases. "Nonsynonymous" variants result in amino acid substitutions in the receptor structure, of which substitution of Gly for Arg at position 16 and Glu for Gln at position 27 are the most clinically relevant. Other polylating ADRB2 expression, thus affecting individual drug responses. Linkage disequilibrium involving polymorphisms in both the coding and noncoding regions may explain the diversity of outcomes regarding functional in vitro studies. To date, analysis by haplotype, rather than genotype, has tended to confuse the issues.
Functional in vitro studies provide the basis by which these polymorphisms are believed to be relevant in vivo. However, follow-up investigations have not substantiated the conventional wisdom that Gly-16 confers increased propensity to downregulation, whereas Glu-27 confers resistance. The in vivo picture is further complicated by the dynamic status of ADRB2s. Paradoxically, downregulation of receptors with exogenous β^sub 2^-agonist drugs may occur more readily in cells that are relatively resistant to downregulation with exposure to endogenous catecholamine.
Numerous studies have highlighted that the Arg-16 variant is associated with an enhanced bronchodilator response in vivo, although the picture is not a consistent one. Outcomes during chronic treatment of asthma with β^sub 2^-agonists have been more consistent. In patients who are homozygous for Arg-16, reduced lung function and increased frequency of exacerbations occur during chronic treatment with short-acting β^sub 2^-agonists. With long-acting β^sub 2^-agonists, the overall clinical benefits may be worse for Arg-16 than for the Gly-16 genotype. Therefore, ADRB2 polymorphisms are an important consideration in assessing individual patients with difficult asthma that may be drug-induced for reasons of ADRB2 genotype. They are also relevant in the design of clinical trials involving β^sub 2^-agonist therapy.[PUBLICATION ABSTRACT]