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

Dahlin A, Litonjua A, Lima JJ, Tamari M, Kubo M, Irvin CG, Peters SP, Tantisira KG - PLoS ONE (2015)

Bottom Line: Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs).The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.Twenty-eight SNP associations from the discovery GWAS were replicated.

View Article: PubMed Central - PubMed

Affiliation: Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 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.

No MeSH data available.


Related in: MedlinePlus

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.
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pone.0129385.g001: 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.

Mentions: The discovery GWAS was conducted in LOCCS and LODO asthmatic cohorts to evaluate the association of patient genotype with 8-week ΔFEV1 following treatment with montelukast (133 patients). Plotted results of the discovery GWAS are shown in Fig 1. Non-white subjects were included, and after adjusting for age, race and gender as covariates, plots of the genomic-control adjusted P values demonstrated no evidence of population stratification. In LOCCS, none of the SNPs exceeded the threshold for genome-wide significance (P = 9.40 x 10−08); however, 25 SNPs approached genome-wide significance (P<10−05), of which the top-ranked SNP (rs12659144) achieved a P value of 2.2 x 10−06, although it did not also replicate in LODO. In LODO, one SNP, rs2247977, achieved genome-wide significance (P = 4.95 x 10−08), although it did not also replicate in LOCCS.


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

Dahlin A, Litonjua A, Lima JJ, Tamari M, Kubo M, Irvin CG, Peters SP, Tantisira KG - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470685&req=5

pone.0129385.g001: 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.
Mentions: The discovery GWAS was conducted in LOCCS and LODO asthmatic cohorts to evaluate the association of patient genotype with 8-week ΔFEV1 following treatment with montelukast (133 patients). Plotted results of the discovery GWAS are shown in Fig 1. Non-white subjects were included, and after adjusting for age, race and gender as covariates, plots of the genomic-control adjusted P values demonstrated no evidence of population stratification. In LOCCS, none of the SNPs exceeded the threshold for genome-wide significance (P = 9.40 x 10−08); however, 25 SNPs approached genome-wide significance (P<10−05), of which the top-ranked SNP (rs12659144) achieved a P value of 2.2 x 10−06, although it did not also replicate in LODO. In LODO, one SNP, rs2247977, achieved genome-wide significance (P = 4.95 x 10−08), although it did not also replicate in LOCCS.

Bottom Line: Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs).The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.Twenty-eight SNP associations from the discovery GWAS were replicated.

View Article: PubMed Central - PubMed

Affiliation: Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 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.

No MeSH data available.


Related in: MedlinePlus