Beta(2)-adrenergic receptor polymorphisms and response to salbutamol among Indian asthmatics*.
BACKGROUND
The beta(2)-adrenergic receptor (beta(2)AR or ADRbeta(2)) is the target for beta(2)-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 beta(2)AR SNPs in responsiveness to beta(2)-agonist therapy in asthma patients.


METHODS
Ten variable SNP sites within a span of 2.193 kb were identified in the beta(2)AR 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 microg of salbutamol. A post-bronchodilator forced expiratory volume in one second (FEV(1)) change of >or= 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 beta(2)AR gene of an asthmatic patient are significantly associated in the studied Indian population (chi2=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 beta(2)AR gene.


CONCLUSIONS
This study suggests that the SNP at nucleotide position 46 has particular relevance to pharmacogenetics in the Indian population studied.
Kukreti
Ritushree
R
GenoMed Lab, (Gene Quest Laboratory, Nicholas Piramal India Ltd) at Institute of Genomics and Integrative Biology (CSIR), Delhi 110007, India. ritushree @hotmail.com
Bhatnagar
Pallav
P
B-Rao
Chandrika
C
Gupta
Simone
S
Madan
Babita
B
Das
Chinmoyee
C
Guleria
Randeep
R
Athavale
Amita Umesh
AU
Brahmachari
Samir Kumar
SK
Ghosh
Balaram
B
D020121:5' Untranslated Regions / Q000235:genetics; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020121:5' Untranslated Regions; D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D017931:DNA Primers; D018343:Receptors, Adrenergic, beta-2; D000420:Albuterol