title: DNA methylation in the arginase-nitric oxide synthase pathway is associated with exhaled nitric oxide in children with asthma.
abstract: BACKGROUND
  Genetic variation in arginase (ARG) and nitric oxide synthase (NOS) has been associated with exhaled nitric oxide (FeNO) levels in children. Little is known about whether epigenetic variation in these genes modulates FeNO.
  
  
  OBJECTIVE
  To evaluate whether DNA methylation in ARG and NOS genes is associated with FeNO.
  
  
  METHODS
  A subset of 940 participants in the Children's Health Study were selected for this study. Children were eligible if they had FeNO measurements and buccal cells collected on the same day. CpG loci located in the promoter regions of NOS1, NOS2A, NOS3, ARG1, and ARG2 genes were analyzed. Multiple loci in each gene were evaluated individually and averaged together. DNA methylation was measured using a bisulfite-polymerase chain reaction pyrosequencing assay. Linear regression models were used to investigate the association between DNA methylation and FeNO and whether associations differed by asthma status.
  
  
  RESULTS
  DNA methylation in ARG2 was significantly associated with FeNO. A 1% increase in average DNA methylation of ARG2 was associated with a 2.3% decrease in FeNO (95% confidence interval, -4 to -0.6). This association was significantly larger in children with asthma (%diff = -8.7%) than in children with no asthma (%diff = -1.6%; p(int) = 0.01). Differences in FeNO by asthma status were also observed for ARG1 (%diff(asthma) = -4.4%; %diff(non-asthma) = 0.3%; p(int) = 0.02). DNA methylation in NOS genes was not associated with FeNO.
  
  
  CONCLUSIONS
  DNA methylation in ARG1 and ARG2 is associated with FeNO in children with asthma and suggests a possible role for epigenetic regulation of nitric oxide production.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. breton@usc.edu
authors.forename: Carrie V
authors.initials: CV
authors.lastname: Breton
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.forename: Muhammad T
authors.initials: MT
authors.lastname: Salam
authors.forename: Kim
authors.initials: K
authors.lastname: Siegmund
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
mesh_terms: D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D001249:Asthma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D001944:Breath Tests; D002648:Child; D019175:DNA Methylation; D045853:Exhalation; D005260:Female; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001119:Arginase