title: Genetic and epigenetic variations in inducible nitric oxide synthase promoter, particulate pollution, and exhaled nitric oxide levels in children.
abstract: BACKGROUND
  Inducible nitric oxide synthase (iNOS; encoded by nitric oxide synthase isoform 2 [NOS2]) is the major enzyme for nitric oxide synthesis in airways. As such, measurement of fractional concentration of exhaled nitric oxide (Feno) provides an in vivo assessment of iNOS activity. Short-term exposure to air pollution, haplotypes, and DNA methylation in the NOS2 promoter has been associated independently with iNOS expression, Feno levels, or both.
  
  
  OBJECTIVE
  We aimed to examine the effects of ambient air pollutants, NOS2 promoter haplotypes, and NOS2 promoter methylation on Feno levels in children.
  
  
  METHODS
  We selected 940 participants in the Children's Health Study who provided buccal samples and had undergone Feno measurement on the same day. DNA methylation was measured with a bisulfite-PCR Pyrosequencing assay. Seven single nucleotide polymorphisms captured the haplotype diversity in the NOS2 promoter. Average particulate matter with an aerodynamic diameter of 2.5 μm or less (PM(2.5)) and 10 μm (PM(10)) or less and ozone and nitrogen dioxide levels 7 days before Feno measurement were estimated based on air pollution data obtained at central monitoring sites.
  
  
  RESULTS
  We found interrelated effects of PM(2.5), NOS2 promoter haplotypes, and iNOS methylation on Feno levels. Increased 7-day average PM(2.5) exposure was associated with lower iNOS methylation (P = .01). NOS2 promoter haplotypes were globally associated with NOS2 promoter methylation (P = 6.2 × 10(-8)). There was interaction among 1 common promoter haplotype, iNOS methylation level, and PM(2.5) exposure on Feno levels (P(interaction) = .00007).
  
  
  CONCLUSIONS
  Promoter variants in NOS2 and short-term PM(2.5) exposure affect iNOS methylation. This is one of the first studies showing contributions of genetic and epigenetic variations in air pollution-mediated phenotype expression.
authors: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, Calif 90089, USA. msalam@usc.edu
authors: Muhammad T
authors: MT
authors: Salam
authors: Hyang-Min
authors: HM
authors: Byun
authors: Fred
authors: F
authors: Lurmann
authors: Carrie V
authors: CV
authors: Breton
authors: Xinhui
authors: X
authors: Wang
authors: Sandrah P
authors: SP
authors: Eckel
authors: Frank D
authors: FD
authors: Gilliland
mesh_terms: D000293:Adolescent; D000328:Adult; D000393:Air Pollutants / Q000032:analysis / Q000633:toxicity*; D000397:Air Pollution / Q000009:adverse effects; D002648:Child; D019175:DNA Methylation; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D045853:Exhalation; D005260:Female; D059647:Gene-Environment Interaction; D006239:Haplotypes; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D052638:Particulate Matter / Q000032:analysis / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D013997:Time Factors; D055815:Young Adult
chemical_list: D000393:Air Pollutants; D052638:Particulate Matter; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II