title: Genetic association analyses of nitric oxide synthase genes and neural tube defects vary by phenotype.
abstract: 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.
authors: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina.
authors: Karen L
authors: KL
authors: Soldano
authors: Melanie E
authors: ME
authors: Garrett
authors: Heidi L
authors: HL
authors: Cope
authors: J Michael
authors: JM
authors: Rusnak
authors: Nathen J
authors: NJ
authors: Ellis
authors: Kaitlyn L
authors: KL
authors: Dunlap
authors: Marcy C
authors: MC
authors: Speer
authors: Simon G
authors: SG
authors: Gregory
authors: Allison E
authors: AE
authors: Ashley-Koch
mesh_terms: D005838:Genotype; D006239:Haplotypes; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009436:Neural Tube Defects / Q000235:genetics*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: MTHFR; NOS1; NOS2; NOS3; NTD; anencephaly; neural tube defect; spina bifida