Soldano Karen L, Garrett Melanie E, Cope Heidi L, Rusnak J Michael, Ellis Nathen J, Dunlap Kaitlyn L, Speer Marcy C, Gregory Simon G, Ashley-Koch Allison E
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina.
Birth Defects Res B Dev Reprod Toxicol. 2013 Oct;98(5):365-73. doi: 10.1002/bdrb.21079. Epub 2013 Dec 9.
Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes.
神经管缺陷（NTDs）是由胚胎发育早期神经管闭合不当引起的。据推测，NTDs有复杂的遗传起源，并且已经提出了许多候选基因。一氧化氮合酶3（NOS3）G594T多态性与脊柱裂风险有关，并且还观察到该单核苷酸多态性（SNP）与亚甲基四氢叶酸还原酶（MTHFR）C677T多态性之间的相互作用。为了评估NTDs发生过程中NO途径的其他遗传变异，我们研究了所有三个NOS基因：NOS1、NOS2和NOS3。我们使用74５个家庭中的3109个白种人样本，在整个数据集中以及特定表型亚组中评估了关联性。测试了NOS基因中的单倍型标签SNP与NTD亚型的遗传关联性，包括主要效应以及与MTHFR C677T多态性的相互作用。在所有三个NOS基因中，均发现与所有亚型存在名义上的主要效应关联性，并且在所有三个NOS基因的SNP与MTHFR C677T之间观察到了相互作用。与之前的报告不同，我们数据集中最显著的关联性是与颅部亚型以及NOS2中rs4795067的AG基因型有关（p = 0.0014），以及NOS1中rs9658490的G等位基因与MTHFR 677TT基因型之间的相互作用（p = 0.0014）。我们的数据扩展了先前的发现，表明所有三个NOS基因不仅通过与MTHFR的相互作用，而且独立地在脊柱裂以及所有NTD亚型的风险中发挥作用。
