Breton Carrie V, Park Caron, Siegmund Kim, Gauderman W James, Whitfield-Maxwell Lora, Hodis Howard N, Avol Ed, Gilliland Frank D
Department of Preventive Medicine and Atherosclerosis Research Unit, University of Southern California, Los Angeles, CA.
Circ Cardiovasc Genet. 2014 Apr;7(2):116-22. doi: 10.1161/CIRCGENETICS.113.000320. Epub 2014 Mar 12.
Nitric oxide (NO) plays an important role in cardiovascular health by maintaining and regulating vascular tone and blood flow. Epigenetic regulation of NO synthase (NOS), the genes responsible for NO production, may affect cardiovascular disease, including the development of atherosclerosis in children.
We measured percentage DNA methylation using bisulfite conversion and pyrosequencing assays on DNA from buccal cells provided by 377 participants of the Children's Health Study on whom carotid artery intima-media thickness (CIMT) measurements were also collected. We examined a total of 16 CpG loci located within NOS1, NOS2A, NOS3, ARG1, and ARG2 genes responsible for NO production. CIMT was measured using high-resolution B-mode carotid ultrasound. The association between percentage DNA methylation in ARG and NOS genes with CIMT was evaluated using linear regression adjusted for sex, ethnicity, body mass index, age at CIMT, town of residence, and experimental plate for pyrosequencing reactions. Differences in the association by ethnicity and ancestral group were also evaluated. For a 1% increase in average DNA methylation of NOS1, CIMT increased by 1.2 μm (P=0.02). This association was greater in Hispanic children of Native American descent (β=2.3; P=0.004) than in non-Hispanic whites (β=0.3; P=0.71) or Hispanic whites (β=1.0; P=0.35).
DNA methylation of NOS1 has a plausible role in atherogenesis through regulation of NO production, although ancestry may alter the magnitude of this association.
一氧化氮（NO）通过维持和调节血管张力及血流，在心血管健康中发挥重要作用。负责产生NO的一氧化氮合酶（NOS）基因的表观遗传调控可能会影响心血管疾病，包括儿童动脉粥样硬化的发展。
我们使用亚硫酸氢盐转化和焦磷酸测序分析法，对来自儿童健康研究的377名参与者的颊细胞DNA进行了DNA甲基化百分比测量，同时还收集了他们的颈动脉内膜中层厚度（CIMT）测量值。我们总共检测了位于负责NO产生的NOS1、NOS2A、NOS3、ARG1和ARG2基因内的16个CpG位点。使用高分辨率B型颈动脉超声测量CIMT。使用线性回归评估ARG和NOS基因中DNA甲基化百分比与CIMT之间的关联，并对性别、种族、体重指数、CIMT测量时的年龄、居住城镇以及焦磷酸测序反应的实验板进行了调整。还评估了按种族和祖先群体划分的关联差异。NOS1平均DNA甲基化增加1%，CIMT增加1.2μm（P=0.02）。这种关联在美洲原住民后裔的西班牙裔儿童中（β=2.3；P=0.004）比在非西班牙裔白人（β=0.3；P=0.71）或西班牙裔白人（β=1.0；P=0.35）中更强。
NOS1的DNA甲基化可能通过调节NO产生在动脉粥样硬化形成中发挥作用，尽管祖先可能会改变这种关联的程度。
