Pharmacogenetics of β2 adrenergic receptor gene polymorphisms, long-acting β-agonists and asthma.

Adrenergic β2 receptor (ADRβ2) agonists are widely used in asthma. Approximately 10% of patients have severe, poorly controlled disease despite extensive use of ADRβ2 agonists. Variations in responses to ADRβ2 agonists can, in part, be attributed to genetic variation, with 49 different polymorphisms having been identified for the ADRβ2 gene. Although clear associations exist between ADRβ2 gene polymorphisms, such as +46G>A, and patient response, the importance of these polymorphisms remains controversial. Patient selection, the number of polymorphisms analysed, differences in the type/dose of ADRβ2 agonist, use of inhaled corticosteroids and population sizes have all varied. Most studies were limited to mild or moderate asthmatics using ADRβ2 agonists sparingly. It is difficult to extrapolate from these studies to individual patients who have severe asthma, use a variety of ADRβ2 agonists and do so frequently. The extent to which ADRβ2 gene polymorphisms are relevant to asthma management needs further review, both clinically and at the molecular level. In vitro studies have helped to define the functional changes induced by specific ADRβ2 gene polymorphisms, including 3'-untranslated region poly-C repeat. The resulting ADRβ2 gene haplotypes (rather than genotypes), the interactions among ADRβ2 gene haplotypes and variations in the chemistry of different agonists deserve more detailed assessment. Responses to ADRβ2 agonists depend on effective downstream signalling following ADRβ2 activation and also on receptor regulation. Studies on other regulators of ADRβ2 receptor signalling and trafficking may be equally important in understanding the functional role of ADRβ2 gene polymorphisms. The role of ADRβ2 gene polymorphisms in the pathogenesis and management of severe asthma cannot be clearly defined until more specific and targeted research studies are performed.