DNA Methylation in the Arginase-Nitric Oxide Synthase Pathway Is Associated with Exhaled Nitric Oxide in Children with Asthma
DNA Methylation in the Arginase-Nitric Oxide Synthase Pathway Is Associated with Exhaled Nitric Oxide in Children with Asthma
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DOI：
10.1164/rccm.201012-2029oc
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发表时间：
2011-07-15
影响因子：
24.7
通讯作者：
Gilliland, Frank D.
中科院分区：
文献类型：
--
作者：
Breton, Carrie V.;Byun, Hyang-Min;Gilliland, Frank D.
理论基础：精氨酸酶(ARG)和一氧化氮合酶(NOS)的遗传变异与儿童呼出的一氧化氮(FeNO)水平有关。这些基因的表观遗传变异是否影响FeNO尚不清楚。目的：评估ARG和NOS基因的DNA甲基化是否与FeNO相关。如果儿童在同一天进行FeNO测量和口腔细胞采集，就符合条件。分析了NOS1、NOS2A、NOS3、ARG1和ARG2基因启动子区域的CpG基因座。每个基因中的多个座位被单独评估，并一起平均。用亚硫酸氢盐-聚合酶链式反应焦磷酸测序法测定DNA甲基化。用线性回归模型研究DNA甲基化与FeNO之间的关系，以及这种联系是否因哮喘状态而不同。测量和主要结果：ARG2中的DNA甲基化与FeNO显著相关。ArG2平均DNA甲基化增加1%与FeNO减少2.3%相关(95%可信区间，-4至-0.6)。哮喘儿童的这种关联性(%diff=-8.7%)明显大于非哮喘儿童(%diff=-1.6%；p(Int)=0.01)。不同哮喘状态的ARG1FeNO也有差异(%diff(哮喘)=-4.4%；%diff(非哮喘)=0.3%；p(Int)=0.02)。结论：ARG1和ARG2基因的DNA甲基化与哮喘患儿的FeNO密切相关，提示其可能参与了对一氧化氮生成的表观遗传调控。
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.