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

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

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).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4470685&req=5

pone.0129385.g002: 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).

Mentions: The top-ranked SNP, rs6475448, achieved genome-wide significance (combined P = 1.97 x 10−09) (Table 2). Patients from all four studies who were homozygous for rs6475448 showed markedly increased mean ΔFEV1 from baseline in response to montelukast (Fig 2). The largest increase between the variant homozygous and reference genotypes was observed for LOCCS, wherein the rs6475448-AA was associated with a LS-mean ΔFEV1 of 344 mL vs. -4.66 mL for rs6475448-GG, followed by CLIC (285 mL for rs6475448-AA vs. -31.7 mL for rs6475448-GG), PACT (101 mL for rs6475448-AA vs. -10.6 mL for rs6475448-GG) and LODO (172 mL for rs6475448-AA vs. 192 mL for rs6475448-GG) (Fig 2).


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)

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).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0129385.g002: 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).
Mentions: The top-ranked SNP, rs6475448, achieved genome-wide significance (combined P = 1.97 x 10−09) (Table 2). Patients from all four studies who were homozygous for rs6475448 showed markedly increased mean ΔFEV1 from baseline in response to montelukast (Fig 2). The largest increase between the variant homozygous and reference genotypes was observed for LOCCS, wherein the rs6475448-AA was associated with a LS-mean ΔFEV1 of 344 mL vs. -4.66 mL for rs6475448-GG, followed by CLIC (285 mL for rs6475448-AA vs. -31.7 mL for rs6475448-GG), PACT (101 mL for rs6475448-AA vs. -10.6 mL for rs6475448-GG) and LODO (172 mL for rs6475448-AA vs. 192 mL for rs6475448-GG) (Fig 2).

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

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