Effect of beta2-adrenergic receptor gene (ADRB2) 3'-untranslated region polymorphisms on inhaled corticosteroid/long-acting beta2-adrenergic agonist response
Evidence suggests that variation in the length of the poly-C repeat in the 3'-untranslated region (UTR) of the beta2-adrenergic receptor gene (ADRB2) may contribute to interindividual variation in beta-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length.
The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the beta2-adrenergic receptor gene (ADRB2) 3'UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting beta2-adrenergic agonist (ICS/LABA) combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response.
Methods:
In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (NCT00242775; AstraZeneca study code: SD-039-0735), sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed.
Results:
Poly-C repeat genotypes were assigned in 97% (2,192/2,250) of patients.
Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides.
Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed.
Patients'pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype.
Conclusions:
The extensive sequence diversity present in the poly-C repeat region of the ADRB2 3'UTR did not predict therapeutic response to ICS/LABA therapy.
Author: Helen J AmbroseRachael M LawranceCarl J CresswellMitchell GoldmanDeborah A MeyersEugene R Bleecker Credits/Source: Respiratory Research 2012, 13:37
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