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

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

doi:10.1016/j.ymgme.2012.09.020

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

Journal article

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

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

Molecular genetics and metabolism, Vol.107(3), pp.592-595

11/2012

DOI: 10.1016/j.ymgme.2012.09.020

PMCID: PMC3704723

PMID: 23059057

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Abstract

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.

BH4

GCH1 gene

GTP cyclohydrolase I

Haplotype

Neural tube defects

Tetrahydrobiopterin

Details

Title: Subtitle: A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study
Creators: Philip J Lupo - Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA
Claudia Chapa - Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA
Darryl Nousome - Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas, USA
Cody Duhon - Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA
Mark A Canfield - Texas Department of State Health Services, Austin, TX, USA
Gary M Shaw - Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
Richard H Finnell - Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA
Huiping Zhu - Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA
National Birth Defects Prevention Study
Contributors: Paul A Romitti (Contributor) - University of Iowa, Epidemiology
Resource Type: Journal article
Publication Details: Molecular genetics and metabolism, Vol.107(3), pp.592-595
DOI: 10.1016/j.ymgme.2012.09.020
PMID: 23059057
PMCID: PMC3704723
NLM abbreviation: Mol Genet Metab
ISSN: 1096-7192
eISSN: 1096-7206
Publisher: Elsevier Inc
Grant note: name: National Institute of Child Health and Development (NICHD); name: Centers for Disease Control and Prevention (CDC) to the Centers for Birth Defects Research and Prevention, award: PA 96043, PA 02081, FOA DD09-001; name: CDC Excellence Award, award: U01/DD000494, U50/CCU925286, NIH R01 NS 050249, HD 067244, NS 076465
Language: English
Date published: 11/2012
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9984214684402771

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