TY - JOUR
T1 - Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in Asthma
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.
N1 - Publisher Copyright:
© 2015 Dahlin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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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U2 - 10.1371/journal.pone.0129385
DO - 10.1371/journal.pone.0129385
M3 - Article
C2 - 26083242
AN - SCOPUS:84939239612
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 6
M1 - e0129385
ER -