Polymorphisms of the beta2-adrenergic receptor and asthma

Several missense mutations (polymorphisms) within the coding block of the beta-adrenergic receptor (beta2AR) gene on chromosome 5q31 have been identified in the human population. In studies utilizing site-directed mutagenesis and recombinant expression, three loci at amino acid positions 16, 27, and 164 have been found to significantly alter receptor function. The Ile164 form displays altered coupling to adenylyl cyclase, the Gly16 receptor displays enhanced agonist-promoted downregulation, and the Glu27 form is resistant to downregulation. The frequencies of these various forms of the beta2AR are not different in asthmatics than in normal populations. However, given the importance of beta2AR in modulating lung function, studies have been carried out to determine if polymorphic forms may play roles in promoting asthmatic phenotypes, establishing bronchial hyperreactivity, or influencing the response to acute or chronic beta-agonist therapy. The results of case-control and family studies to date support these notions. Thus beta2AR polymorphisms act as disease modifiers in asthma and represent one of probably many genetic variables involved in the pathophysiology of asthma.