β2-adrenergic receptor polymorphisms and response to salbutamol among Indian asthmatics∗

Abstract

Introduction: The β2-adrenergic receptor (β2AR or ADRβ2) is the target for β2-agonist drugs used for bronchodilation in asthma and other respiratory diseases. The aim of this study was to identify common single nucleotide polymorphisms (SNPs) and haplotypes in asthmatics and healthy individuals from an Indian population, and determine the influence of β2AR SNPs in responsiveness to β2-agonist therapy in asthma patients. Methods: Ten variable SNP sites within a span of 2.193 kb were identified in the β2AR gene by sequencing and genotyping 374 bronchial asthma patients and healthy individuals from an Indian population. Spirometry tests were performed on 80 unrelated patients before and after administration of 200 μg of salbutamol. A postbronchodilator forced expiratory volume in one second (FEV1) change of ≥ 15.3% was considered a good response, and a change of < 15.3% was defined as a poor response, to salbutamol. Results: The pattern of linkage disequilibrium between the ten SNPs showed a single, linked SNP block consisting of sites -468, -367, -47, -20, and 79 having strong linkage disequilibrium, while the SNPs at sites -1023, -654, 46, 252, and 523 showed very low linkage with one another and with the linked region. The SNPs were found to be organized into 16 haplotypes in the studied population. We found that patients with a homozygous Arg-16 form at nucleotide position 46 are poor responders with probability of 0.81, and patients with a homozygous Gly-16 form are good responders with a probability of 0.73. The responder status to salbutamol treatment and the genotype at nucleotide position 46 in β2AR gene of an asthmatic patient are significantly associated in the studied Indian population (χ2 = 9.98, df = 2, p = 0.0068). Most importantly, this association for responsiveness to salbutamol at nucleotide position 46 is independent of other SNPs in the β2AR gene. Conclusion: This study suggests that the SNP at nucleotide position 46 has particular relevance to pharmacogenetics in the Indian population studied.