Cysteinyl Leukotriene Receptor 1 and Health Effects of Particulate Exposure in Asthma.

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 μm 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 μg 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.