A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study.
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.
Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA.
Philip J
PJ
Lupo
Claudia
C
Chapa
Darryl
D
Nousome
Cody
C
Duhon
Mark A
MA
Canfield
Gary M
GM
Shaw
Richard H
RH
Finnell
Huiping
H
Zhu
D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency; D002675:Child, Preschool; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009436:Neural Tube Defects / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D011795:Surveys and Questionnaires; D014481:United States / Q000453:epidemiology
D001708:Biopterins; D006136:GTP Cyclohydrolase; C003402:sapropterin