Dataset Information

5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci.

ABSTRACT: The two classes of leukotriene modifiers work by inhibiting different portions of the same pathway. We hypothesized that single nucleotide polymorphisms (SNPs) in genes associated with response to montelukast (a cys-leukotriene receptor antagonist) would also be associated with response to zileuton (a 5-lipoxygenase inhibitor). We genotyped 26 SNPs that had previously been interrogated for association with montelukast response in five candidate genes (ABCC1, ALOX5, CYSLTR1, LTA4H, LTC4S) in a population of 577 asthmatics who participated in a clinical trial comparing intermittent and continuous-release zileuton to placebo. After adjusting for age and sex, six SNPs in three genes were associated with longitudinal forced expiratory volume at 1 s in response to zileuton (P values 0.005-0.05). After adjusting for age and sex, six SNPs in three genes were associated with longitudinal forced expiratory volume at 1 s in response to zileuton (P values 0.005-0.05), including two SNPs (ALOX5 rs2115819 and ABCC1 rs119774) that we had previously reported as associated with FEV1 response to montelukast. Thus, the lung function response to zileuton is modulated by several of the loci that also influence montelukast response.

SUBMITTER: Tantisira KG

PROVIDER: S-EPMC2731688 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci.

Tantisira Kelan G KG Lima John J Sylvia Jody J Klanderman Barbara B Weiss Scott T ST

Pharmacogenetics and genomics 20090301 3

The two classes of leukotriene modifiers work by inhibiting different portions of the same pathway. We hypothesized that single nucleotide polymorphisms (SNPs) in genes associated with response to montelukast (a cys-leukotriene receptor antagonist) would also be associated with response to zileuton (a 5-lipoxygenase inhibitor). We genotyped 26 SNPs that had previously been interrogated for association with montelukast response in five candidate genes (ABCC1, ALOX5, CYSLTR1, LTA4H, LTC4S) in a po ...[more]

PMID: 19214143

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Project description:Rationale: Acute exposure to ambient particle matter is associated with increased levels of the cysteinyl leukotriene (CysLT) biomarker, urinary leukotriene E4 (uLTE4), in subjects with asthma. Objectives: The role of CysLTs in mediating asthma worsening after particulate matter exposures was explored. Methods: Daily concentrations of particulate matter of 2.5 ?m and smaller diameter (PM2.5) and repeated measurements of albuterol use over a 5-month period were collected in 44 urban school children with persistent asthma. DNA was analyzed for gene polymorphisms on genes involved in the CysLT pathway to identify gene–environment interactions. An experimental challenge study in 16 adults with mild, nonpersistent asthma was performed to define biological pathways explaining these gene–environment interactions. Subjects in the challenge study were exposed on two different days to filtered air or diesel exhaust (300 ?g PM2.5/m3). FEV1 and CysLT-related gene DNA methylation and messenger RNA expression changes were measured before and 6 hours after exposure challenges. Results: In school children with asthma, associations between PM2.5 and school-time albuterol usage were significantly greater in those with the variant C allele in the CysLT receptor 1 (CysLTR1) rs320995 locus (5.4% increase per interquartile range PM2.5 increase) compared with those homozygous for the wild-type T allele (1.6% decrease; P?=?0.005 for allele?×?PM2.5 interaction). In the challenge study, declines in forced expiratory volume in 1 second after diesel exhaust exposure were associated with lower CysLTR1 expression (r2?=?0.52; P?=?0.01), which, in turn, was associated with decreased leukotriene C4 synthase cg1631890 (P?=?0.02) and increased CysLTR1 cg26848126 (P?=?0.01) methylation, as assessed in a multivariable model (r2?=?0.69). Conclusions: Health effects of acute particulate exposure on asthma are associated with changes in CysLTR1 expression and methylation of CpG sites on CysLTR1 and leukotriene C4 synthase genes.

Dataset Information

5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci.

Publications

5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci.

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