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

Respiratory Research

Eugene R Bleecker¹  Deborah A Meyers¹  Mitchell Goldman³  Carl J Cresswell²  Rachael M Lawrance²  Helen J Ambrose² 

[1] Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC, 27157, USA;AstraZeneca, Alderley Park, UK;AstraZeneca LP, Wilmington, DE, USA

关键词: Poly-C repeat;    3′ untranslated region;    β₂-adrenergic receptor;    Polymorphism;    Genotype;    Inhaled corticosteroid;    β₂-agonist;    Asthma;   

Others  :  796725
DOI  :  10.1186/1465-9921-13-37

 received in 2011-10-14, accepted in 2012-05-04,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Ambrose et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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