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A GCH1 Haplotype and Risk of Neural Tube Defects in the National Birth Defects Prevention Study
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Details:
  • Corporate Authors:
    The National Birth Defects Prevention Study
  • Pubmed ID:
    23059057
  • Pubmed Central ID:
    PMC3704723
  • Description:
    Tetrahydrobiopterin (BH(4)) is an essential cofactor and an important cellular antioxidant. BH(4) deficiency has been associated with diseases whose etiologies stem from excessive oxidative stress. GTP cyclohydrolase I (GCH1) catalyzes the first and rate-limiting step of de novo BH(4) synthesis. A 3-SNP haplotype in GCH1 (rs8007267, rs3783641, and rs10483639) is known to modulate GCH1 gene expression levels and has been suggested as a major determinant of plasma BH(4) bioavailability. As plasma BH(4) bioavailability has been suggested as a mechanism of neural tube defect (NTD) teratogenesis, we evaluated the association between this GCH1 haplotype and the risk of NTDs. Samples were obtained from 760 NTD case-parent triads included in the National Birth Defects Prevention Study (NBDPS). The three SNPs were genotyped using TaqMan® SNP assays. An extension of the log-linear model was used to assess the association between NTDs and both offspring and maternal haplotypes. Offspring carrying two copies of haplotype C-T-C had a significantly increased NTD risk (risk ratio [RR]=3.40, 95% confidence interval [CI]: 1.02-11.50), after adjusting for the effect of the maternal haplotype. Additionally, mothers carrying two copies of haplotype C-T-C had a significantly increased risk of having an NTD-affected offspring (RR=3.46, 95% CI: 1.05-11.00), after adjusting for the effect of the offspring haplotype. These results suggest offspring and maternal variation in the GCH1 gene and altered BH(4) biosynthesis may contribute to NTD risk.

  • Document Type:
  • Collection(s):
  • Funding:
    FOA DD09-001/DD/NCBDD CDC HHS/United States
    HD 067244/HD/NICHD NIH HHS/United States
    NS 076465/NS/NINDS NIH HHS/United States
    P01 HD067244/HD/NICHD NIH HHS/United States
    PA 02081/PHS HHS/United States
    PA 96043/PHS HHS/United States
    R01 NS 050249/NS/NINDS NIH HHS/United States
    R01 NS050249/NS/NINDS NIH HHS/United States
    R21 HD 058912/HD/NICHD NIH HHS/United States
    R21 HD058912/HD/NICHD NIH HHS/United States
    U01/DD000494/DD/NCBDD CDC HHS/United States
    U50/CCU925286/PHS HHS/United States
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