1. Effect of β2-adrenergic receptor gene (ADRB2) 3′ untranslated region polymorphisms on inhaled corticosteroid/long-acting β2-adrenergic agonist response
- Author
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Mitchell Goldman, Eugene R. Bleecker, Deborah A. Meyers, Rachael Lawrance, Carl John Cresswell, and Helen Ambrose
- Subjects
Pulmonary and Respiratory Medicine ,Agonist ,Untranslated region ,Adult ,Male ,β2-agonist ,β2-adrenergic receptor ,medicine.medical_specialty ,Poly-C repeat ,Genotype ,medicine.drug_class ,Molecular Sequence Data ,Adrenergic ,Context (language use) ,Biology ,Pharmacology ,Young Adult ,Polymorphism (computer science) ,Adrenal Cortex Hormones ,Inhaled corticosteroid ,Internal medicine ,medicine ,Humans ,Polymorphism ,Receptor ,Genotyping ,3' Untranslated Regions ,Adrenergic beta-2 Receptor Agonists ,lcsh:RC705-779 ,Polymorphism, Genetic ,Base Sequence ,Three prime untranslated region ,Research ,lcsh:Diseases of the respiratory system ,Middle Aged ,Asthma ,Bronchodilator Agents ,Endocrinology ,Treatment Outcome ,Tandem Repeat Sequences ,Drug Therapy, Combination ,Female ,Receptors, Adrenergic, beta-2 ,3′ untranslated region - Abstract
Background Evidence 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. Methods In 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. 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.
- Published
- 2012