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. 2015 Jun 17;10(6):e0129385.
doi: 10.1371/journal.pone.0129385. eCollection 2015.

Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma

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Free PMC article

Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma

Amber Dahlin et al. PLoS One. .
Free PMC article

Abstract

Background: Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics.

Methods: Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.

Results: Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10-09), and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV1 from baseline in response to montelukast.

Conclusions: Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.

Conflict of interest statement

Competing Interests: GlaxoSmithKline supported the conduct of the LOCCS Trial by providing funds to the American Lung Association. The authors received no relevant funding or financial support from GSK. There are no patents, products in development or marketed products related to this manuscript to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Results of the discovery GWAS.
Manhattan plots (A and B) contain −log P values (y-axis) associated with 8-week change in FEV1 after montelukast treatment, for 532,264 genotyped SNPs organized by chromosome (x-axis), for LOCCS (A) and LODO (B). The threshold for genome-wide significance and suggestive genome-wide significance are indicated as blue and red lines, respectively, in the Manhattan plots. Q-Q plots (C and D) demonstrate the observed −log P values vs. expected −log P values, for SNPs from LOCCS (C) and LODO (D) populations. In all plots, individual SNPs are represented as filled circles.
Fig 2
Fig 2. Improvement in lung function related to montelukast treatment, by rs6475448 genotype.
The least-squares (LS) means (adjusted for study, race and gender) and 95% confidence intervals for ΔFEV1 related to montelukast treatment were generated using R (http://cran.r-project.org/web/packages/lsmeans/lsmeans.pdf), and plotted for each study (panels), by rs6475448 genotypes: homozygous reference (“GG”: LOCCS = 32; LODO = 38; CLIC = 25; PACT = 65), heterozygous (“GA”: LOCCS = 28; LODO = 21; CLIC = 30; PACT = 75) and homozygous variant (“AA”: LOCCS = 9; LODO = 5; CLIC = 5; PACT = 5).

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