title: Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma.
abstract: Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tong
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mauger
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Tantisira
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Israel
authors.affiliation: National Jewish Health and University of Colorado School of Medicine, Denver, CO, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Szefler
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Chinchilli
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Boushey
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Lazarus
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wu
mesh_terms: D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D005938:Glucocorticoids