fi2-Adrenergic Receptor (ft2AR) Polymorphisms and Asthma
The (32AR is expressed on a number of cell types in the lung, including mast cells and bronchial smooth muscle cells. It is the target for b2AR agonists, one of the most effective class of bronchodilating drugs. Altered (32AR expression or function has been shown to accompany asthma by a number of investigators. Liggett and others84 looked for b2AR gene polymorphisms and their association with asthma. Nine polymorphisms were identified, four of which resulted in amino-acid substitutions: Argl6—>Gly, Gln27-Glu, Val34Met and Thrl64—>Ile. Although there was no difference in the prevalence of these polymorphisms between normal subjects and asthmatics, the Argl6—>Gly polymorphism was more prevalent in individuals with steroid-dependent asthma and in those needing immunotherapy. Functional studies revealed no apparent change of receptor function due to the Val34—>Met polymorphism. The other three polymorphisms resulted in distinct changes in receptor function. The Thrl64—>Ile receptor demonstrated reduced affinity for binding to epinephrine, norepinephrine, and displayed decreased maximal stimulation of adenyl cyclase for epinephrine-mediated stimulation.86 Based on this, it may be expected that patients with this polymorphism are less responsive to endogenous or administered (3-agonists, and have more severe asthma. However, this is a rare polymorphism and not enough patients with this polymorphism have been studied to explore this hypothesis. The Argl6-Gly and Gln27>Glu variants demonstrated normal binding affinities to (3-agonists, but displayed altered agonist-induced receptor downregulation. The Argl6—>Gly variant underwent enhanced agonist-induced downregulation, whereas the Gln27-Glu variant underwent significantly less agonist-induced downregulation compared to the wild-type receptor my canadian pharmacy.com
In a study comparing individuals with nocturnal asthma and nonnocturnal asthma, Glyl6 was significantly more prevalent in those with nocturnal asthma. It had been shown previously that circulating neutrophil and lymphocyte b2AR, which are potential markers for (32AR in the lung, decrease at 4 AM compared to 4 pm in patients with nocturnal asthma. No such circadian downregulation was seen in nonnocturnal asthmatics and normal subjects.88 Since Argl6-> Gly variant undergoes enhanced downregulation, it is probable that the greater downregulation of b2AR seen in nocturnal asthmatics may be related to glycine at position 16. Further, patients homozygous for Glyl6 had a much greater loss of bronchod-ilator response after long-term inhaled b2-agonist therapy compared to patients homozygous for Argl6.2 In asthmatic children, Glyl6 was associated with less bronchodilator response compared to Argl6.2 In a study of atopic asthmatics who were segregated based on the presence or absence of BHR to histamine, Glyl6 was strongly associated with bronchial hyperreactivity In contrast, Glu27 variant was associated with lower bronchial reactivity 90 In conclusion, while (32AR polymorphisms are unlikely to represent a major genetic predisposition to asthma, they may influence the expression and severity of asthma and the response to b-agonist therapy.