Genetic variation of the beta(2)-adrenoceptor: its functional and clinical importance in bronchial asthma

Asthma is a polygenic disease for which no clear genotype-phenotype relationships have emerged. In contrast, although not associated with the diagnosis of asthma per se, variant forms of the beta(2)-adrenoceptor (beta2-AR) gene (ADRB2) display functional effects that may be clinically relevant. Single nucleotide polymorphisms (SNPs) of ADBR2 are common and result in amino acid substitutions at positions 16, 27, and 164 of the receptor as well as position 19 of its 5' upstream peptide. These SNPs influence receptor function in vitro, although evidence regarding exact relationships is conflicting. This has raised the possibility that phenotypes such as bronchial hyper-responsiveness (BHR) and responses to (beta2)-agonist drugs may be genetically determined. To date, no unequivocal relationships between SNPs and phenotype have been identified. In some studies the Gly(16) allele has been associated with increased BHR and asthma severity. In others, the Arg(16) allele has been shown to determine acute bronchodilator response and adverse events during long term beta(2)-agonist therapy. The latter may provide the basis for clinical application of this new knowledge. More recently, a small number of frequently occurring, functionally relevant ADRB2 haplotype pairs have been confirmed. These combinations of alleles may be more important in determining genotype/phenotype relationships than individual SNPs, and may explain why earlier investigations have yielded contrasting results. Future studies will be required to clarify the pharmacodynamic effects of ADRB2haplotypes both in vitro and in vivo.