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Clinical Trial
. 2016 Apr;16(2):151-7.
doi: 10.1038/tpj.2015.34. Epub 2015 Jun 2.

Genome-wide Association Study of Leukotriene Modifier Response in Asthma

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Free PMC article
Clinical Trial

Genome-wide Association Study of Leukotriene Modifier Response in Asthma

A Dahlin et al. Pharmacogenomics J. .
Free PMC article

Abstract

Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.

Figures

Figure 1
Figure 1
Quantile–quantile (Q–Q) plots of Abbott populations. Q–Q plots show results for Abbott trial 1 (discovery) (a) and Abbott trial 2 (replication) (b). Lambda (λ) indicates the genomic inflation factor values.
Figure 2
Figure 2
Results of the GWAS of zileuton response. Manhattan plots show GWAS results for the discovery cohort (Abbott trial 1) for additive (a) dominant (b) and recessive (c) genetic models. For each plot, the y axis represents –log10(P-values) for each SNP (gray and black dots), grouped by chromosomes 1–22 (x axis). Horizontal lines in the plots indicate the threshold for suggestive genome-wide significance (P=1 × 10−05).
Figure 3
Figure 3
rs12436663 genotype-dependent change in lung function. The boxplots show ΔFEV1 (L) grouped by rs12436663 genotype: variant genotype (‘AA' (N=11 patients), left), heterozygous genotype (‘AG' (N=151 patients), center) and reference genotype (‘GG' (N=362 patients), right).
Figure 4
Figure 4
Regional association (LD) plot for rs12436663. The regional association plot was generated from the GWAS association data (discovery+replication) with Locus Zoom (http://csg.sph.umich.edu/locuszoom/), specifying a ±200-kb region from rs12436663 (diamond symbol) for all GWAS SNPs (circle symbols), and using the HapMap Phase II CEU version 18 (no LD) as the reference genome build.

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