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. 2012 Nov;107(3):592-5.
doi: 10.1016/j.ymgme.2012.09.020. Epub 2012 Sep 25.

A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study

Philip J Lupo  1 , Claudia Chapa, Darryl Nousome, Cody Duhon, Mark A Canfield, Gary M Shaw, Richard H Finnell, Huiping Zhu; National Birth Defects Prevention Study
Affiliations

A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study

Philip J Lupo et al. Mol Genet Metab. 2012 Nov.

Abstract

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.

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Figures

Figure 1
Figure 1. De novo biosynthesis and regeneration of tetrohydrobiopterin (BH4)
The pathway for the de novo biosynthesis of BH4 from GTP involves GTP cyclohydrolase I (GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTS) and sepiapterin reductase (SPR). GCH1 catalyzes the rate-limiting step. The regeneration requires pterin-4a-carbinolamine dehydratase (PCD) and quinoid dihydropteridine (qBH2) and dihydropteridin reductase (DHPR).
See this image and copyright information in PMC

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