title: Pharmacogenetics of asthma controller treatment.
abstract: The interpatient variability in response to asthma controllers is significant and associates with pharmacogenomic variability. The goal of the present study was to identify novel variants that associate with response to common asthma controllers: fluticasone, combination of fluticasone + salmeterol and montelukast with single nucleotide polymorphisms (SNPs) in β2-adrenergic receptor, corticosteroid and leukotriene pathway candidate genes. Participants in a large clinical trial of step-down strategies volunteered for this pharmacogenetic study. A total of 169 SNPs in 26 candidate genes were genotyped in 189 Caucasian participants with asthma who took either fluticasone (100 μg bid), fluticasone propionate (100 μg) + salmeterol (50 μg) (FP/Salm) or montelukast (5 or 10 mg) each night for 16 weeks. Primary outcomes were the slopes of plots of Asthma Control Questionnaire (ACQ) scores versus time following randomization; and the percent change in percent predicted FEV1 (ΔFEV1%pred) from enrollment to the end of the study. Associations between SNPs and outcomes were analyzed using general linear models. False discovery rate and Bonferroni corrections were used to correct for multiple comparisons. In all, 16 SNPs in seven genes were significantly associated with outcomes. For FP/Salm, three SNPs in CHRM2 associated with ACQ slope (P=2.8 × 10⁻⁵), and rs1461496 in HSPA8 associated with ΔFEV1%pred. For fluticasone, five SNPs in CRHR1 (P=1.9 × 10⁻⁴), and three SNPs in COL2A1 associated with ACQ slope and ΔFEV1%pred, respectively. For montelukast, four SNPs in CHRM2 associated with ΔFEV1%pred and predicted an opposite effect compared with fluticasone (P=9 × 10⁻³). The present study indentified several novel SNPs that associate with response to common asthma controllers, and support further pharmacogenomic study and the use of genetic variants to personalize asthma treatment.
authors.affiliation: ALA-Asthma Clinical Research Center, Jacksonville, FL, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Mougey
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: K G
authors.initials: KG
authors.lastname: Tantisira
authors.forename: K V
authors.initials: KV
authors.lastname: Blake
authors.forename: S P
authors.initials: SP
authors.lastname: Peters
authors.forename: R A
authors.initials: RA
authors.lastname: Wise
authors.forename: S T
authors.initials: ST
authors.lastname: Weiss
authors.forename: J J
authors.initials: JJ
authors.lastname: Lima
mesh_terms: D000085:Acetates / Q000008:administration & dosage; D000280:Administration, Inhalation; D000293:Adolescent; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives; D000730:Androstadienes / Q000008:administration & dosage; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002986:Clinical Trials as Topic; D003521:Cyclopropanes; D004338:Drug Combinations; D005260:Female; D000068298:Fluticasone; D005541:Forced Expiratory Volume; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011804:Quinolines / Q000008:administration & dosage; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D000068299:Salmeterol Xinafoate; D013440:Sulfides
chemical_list: D000085:Acetates; D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D004338:Drug Combinations; D011804:Quinolines; D018343:Receptors, Adrenergic, beta-2; D013440:Sulfides; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; C093875:montelukast; D000420:Albuterol