DNA methylation in the arginase-nitric oxide synthase pathway is associated with exhaled nitric oxide in children with asthma.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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: Carrie V Breton, Hyang-Min Byun, Xinhui Wang, Muhammad T Salam, Kim Siegmund, Frank D Gilliland
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 184 Issue 2 Pg. 191-7 (Jul 15 2011) ISSN: 1535-4970 [Electronic] United States
• PMID: 21512169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Nitric Oxide
• Nitric Oxide Synthase
• Arginase

Topics

• Arginase (genetics, metabolism)
• Asthma (enzymology, genetics, metabolism)
• Breath Tests
• Child
• DNA Methylation
• Exhalation
• Female
• Humans
• Male
• Nitric Oxide (genetics, metabolism)
• Nitric Oxide Synthase (genetics, metabolism)
• Polymerase Chain Reaction
• Statistics, Nonparametric