Effect of β2-adrenergic receptor gene (ADRB2) 3′ untranslated region polymorphisms on inhaled corticosteroid/long-acting β2-adrenergic agonist response

Abstract

BackgroundEvidence suggests that variation in the length of the poly-C repeat in the 3′ untranslated region (3′UTR) of the β2-adrenergic receptor gene (ADRB2) may contribute to interindividual variation in β-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 ADRB2 3′UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA) combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response.MethodsIn 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (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.ResultsPoly-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.ConclusionsThe extensive sequence diversity present in the poly-C repeat region of the ADRB2 3′UTR did not predict therapeutic response to ICS/LABA therapy.

Personalized management of asthma exacerbations: lessons from genetic studies

“…Polymorphisms in ADRB2 have not been found to be associated with fatal or near-fatal asthma[21]. Despite the association of ADRB2 polymorphisms with β2-adrenergic receptor downregulation, ADRB2 polymorphisms and haplotypes have not consistently demonstrated an association with β 2 -agonist treatment response, and their role in the pathogenesis of severe asthma and asthma exacerbations remains unclear[22, 23, 24]. …”

What the Genetic Background of Individuals with Asthma and Obesity Can Reveal: Is β2-Adrenergic Receptor Gene Polymorphism Important?

“…However, a clinical study concerning therapy with a long-acting beta-agonist (LABA) plus inhaled corticosteroid did not show any association with this genotype. 24 …”

Pharmacogenomics of long-acting β2-agonists

“…This variable-length poly-C tract starts at nucleotide 1266 (or 1269); repeats of 10, 11, 12, 13, and, rarely, 14 C are found in Whites and African American patients with asthma, with the highest frequency of 34 and 64%, respectively, for the 13 poly-C repeat [89,91,99]. This sequence is interrupted by two polymorphisms at the 2nd and 10th C-repeat which yields additional haplotypes [89].…”

“…Two haplotypes had both increased b 2 -receptor expression and less b 2 -agonist promoted downregulation and had the fewest poly-C repeats; patients with these haplotypes are speculated to have the best overall response to b 2 -agonist treatment. In a more recent study, the polymorphisms with the poly-C region have been carefully sequenced using novel techniques to identify four new polymorphisms within the region (+1269, +1271, +1272, and +1276) as well as poly-C repeats of 15 and 16 in length [99]. The clinical effects of the poly-C repeats and long-acting b 2 -agonists outcomes are described below.…”

“…Only 1% of the population was African American (73% White, 7% Asian) [99]. The region was carefully sequenced using a novel genotyping method which resulted in identifying longer poly-C repeats (15 and 16) as well as four novel polymorphisms.…”