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

Tetrahydrobiopterin (BH4) is an essential cofactor and an important cellular antioxidant. BH4 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 BH4 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 BH4 bioavailability. As plasma BH4 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 BH4 biosynthesis may contribute to NTD risk. ► Plasma BH4 may be associated with neural tube defects (NTDs). ► GCH1 haplotype affects BH4 bioavailability. ► We evaluated the GCH1 haplotype in 760 NTD trios. ► Offspring with two copies of haplotype C-T-C had a significantly increased NTD risk. ► Mothers with the same haplotype had an increased risk of having an affected child. ► These results suggest variation in the GCH1 haplotype may contribute to NTD risk.