Acute and chronic lung function responses to salmeterol and salmeterol plus fluticasone propionate in relation to Arg16Gly beta(2)-adrenergic polymorphisms.
OBJECTIVE
There is conflicting clinical evidence describing the response to long-acting beta-agonist (LABA) bronchodilators for patients with Arg16Gly beta(2)-adrenergic receptor (ADRB2 ) genotype differences. Furthermore, the role of inhaled corticosteroids (ICS) in modulating Arg16Gly clinical responses is not well understood. The objective of this study was to investigate the effects of Arg16Gly polymorphism on the 12 hour post-dose bronchodilator response to the LABA salmeterol (SAL) or SAL plus fluticasone propionate (FSC) on first administration and following 12 weeks of treatment.


METHODS
Genotyping was retrospectively performed in patients with persistent asthma randomized to SAL or FSC who were participating in three similar double-blind clinical trials of 12 week duration. The primary outcome was area under the curve (AUC) for 12 hour serial FEV(1) by treatment and Arg16Gly genotype, recorded on Day 1 and Week 12. In addition, other single nucleotide polymorphisms (SNPs) associated with asthma outcomes we assessed at positions -47, +79 and +491 as well as common ADRB2 haplotypes.


RESULTS
No statistically significant associations between Arg16Gly genotypes and serial FEV(1) clinical responses to SAL and FSC were observed following acute assessment. In addition, the FEV(1) response was preserved following 12 weeks of treatment with SAL and FSC and was not altered by Arg16Gly genotypes analyzed. These results may not be generalizable to other ethnic groups since they are derived predominantly from Caucasians.


CONCLUSIONS
In subjects with persistent asthma, the ADRB2 Arg16Gly polymorphism does not alter lung function responses to SAL or FSC over the 12 hour dosing interval following acute and chronic dosing.
Yancey
Steven W
SW
GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.
Klotsman
Michael
M
Ortega
Hector G
HG
Edwards
Lisa D
LD
Anderson
Wayne H
WH
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019943:Amino Acid Substitution; D000730:Androstadienes / Q000627:therapeutic use*; D001120:Arginine / Q000235:genetics; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005260:Female; D000068298:Fluticasone; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012129:Respiratory Function Tests; D012189:Retrospective Studies; D000068299:Salmeterol Xinafoate; D055815:Young Adult
D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D001993:Bronchodilator Agents; D017931:DNA Primers; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D004247:DNA; D001120:Arginine; D000068298:Fluticasone; D000420:Albuterol; D005998:Glycine