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PLoS One. 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.

Author information

1
Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
2
Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, United States of America; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
3
Nemours Children's Clinic, Jacksonville, FL, United States of America.
4
Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
5
University of Vermont, Burlington, VT, United States of America.
6
Wake Forest School of Medicine, Winston-Salem, NC, United States of America.

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.

PMID:
26083242
PMCID:
PMC4470685
DOI:
10.1371/journal.pone.0129385
[Indexed for MEDLINE]
Free PMC Article

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