Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in Asthma

Amber Dahlin, Augusto Litonjua, John J. Lima, Mayumi Tamari, Michiaki Kubo, Charles G. Irvin, Stephen P. Peters, Kelan G. Tantisira

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 ΔFEV1from baseline in response to montelukast. Conclusions Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.

Original languageEnglish
Article numbere0129385
JournalPloS one
Volume10
Issue number6
DOIs
Publication statusPublished - 17-06-2015

Fingerprint

montelukast
pharmacogenomics
Genome-Wide Association Study
Pharmacogenetics
asthma
Asthma
Genes
single nucleotide polymorphism
Single Nucleotide Polymorphism
therapeutics
loci
Polymorphism
Leukotriene Antagonists
leukotrienes
Nucleotides
antagonists
Genome
Therapeutics
receptors
genome

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Dahlin, Amber ; Litonjua, Augusto ; Lima, John J. ; Tamari, Mayumi ; Kubo, Michiaki ; Irvin, Charles G. ; Peters, Stephen P. ; Tantisira, Kelan G. / Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in Asthma. In: PloS one. 2015 ; Vol. 10, No. 6.
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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 ΔFEV1from baseline in response to montelukast. Conclusions Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.",
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Dahlin, A, Litonjua, A, Lima, JJ, Tamari, M, Kubo, M, Irvin, CG, Peters, SP & Tantisira, KG 2015, 'Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in Asthma', PloS one, vol. 10, no. 6, e0129385. https://doi.org/10.1371/journal.pone.0129385

Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in Asthma. / Dahlin, Amber; Litonjua, Augusto; Lima, John J.; Tamari, Mayumi; Kubo, Michiaki; Irvin, Charles G.; Peters, Stephen P.; Tantisira, Kelan G.

In: PloS one, Vol. 10, No. 6, e0129385, 17.06.2015.

Research output: Contribution to journalArticle

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AU - Dahlin, Amber

AU - Litonjua, Augusto

AU - Lima, John J.

AU - Tamari, Mayumi

AU - Kubo, Michiaki

AU - Irvin, Charles G.

AU - Peters, Stephen P.

AU - Tantisira, Kelan G.

PY - 2015/6/17

Y1 - 2015/6/17

N2 - 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 ΔFEV1from baseline in response to montelukast. Conclusions Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.

AB - 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 ΔFEV1from baseline in response to montelukast. Conclusions Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.

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