Neural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene–Gene and Gene–Environment Interactions

Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 11/2006; 114(10):1547-52. DOI: 10.1289/ehp.9166
Source: PubMed


Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results.
Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation.
In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase.
Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission.
BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene-gene interactions in large data sets.

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    • "To test if the functional predictions were likely to be biologically relevant, we searched the literature for prior evidence that the predicted regulatory elements were previously associated with any human disorder. Out of the 38 regulatory elements that may be influenced by the expression quantitative trait loci SNPs, 11 have previously been associated with hematologic cancers or, supporting the biologic plausibility of our findings (Boyles et al., 2006; Fan et al., 2008; Boyles et al., 2008; Paré et al., 2009; Martinez et al., 2009; Steinmaus et al., 2010; Metayer et al., 2011; Wernimont et al., 2011; Tilley et al., 2012). "
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    ABSTRACT: Cystathionine β-synthase is an essential enzyme of the trans-sulfuration pathway that condenses serine with homocysteine to form cystathionine. Missense mutations in CBS are the major cause of inherited homocystinuria, and the detailed effect of disease associated amino acid substitutions on the structure and stability of human CBS is yet unknown. Here, we apply a unique approach in combining in silico tools and molecular dynamics simulation to provide structural and functional insight into the effect of SNP on the stability and activity of mutant CBS. In addition, principal component analysis and free energy landscape were used to predict the collective motions, thermodynamic stabilities and essential subspace relevant to CBS function. The obtained results indicate that C109R, E176K and D376N mutations have the diverse effect on dynamic behavior of CBS protein. We found that highly conserved D376N mutation, which is present in the active pocket, affects the protein folding mechanism. Our strategy may provide a way in near future to understand and study effects of functional nsSNPs and their role in causing homocystinuria.
    Frontiers of Biology 06/2014; 9(6). DOI:10.1007/s11515-014-1320-4
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    • "Neural tube defects (NTDs) are a group of congenital malformations including spina bifida, anencephaly, and encephalocele, which arise during the process of neurulation between the third and fourth weeks of human pregnancy (1, 2). NTDs contribute to miscarriage, infant mortality, and serious disability (3). "
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    ABSTRACT: Background:Neural tube defects (NTDs) including spina bifida and anencephaly are the second most common birth defects with 2.8 per 1000 births in northern Iran.Objectives:This study was conducted to determine the risk factors of neural tube defects in Gorgan, north of Iran.Patients and Methods:This hospital-based, case-control study was carried out on all NTD-affected pregnancies (n = 59) during February 2007 - August 2010, and 160 healthy pregnancies were selected via convenient sampling method in three hospitals in Gorgan, north of Iran. Risk factors including maternal body mass index (BMI), season of birth, gender of the newborn, mother’s age, ethnicity, consanguineous marriage, folic acid consumption, nutrition, habitat, and education, were assessed through interviews with mothers. Univariate and multivariate logistic regression analyses were used to estimate the risks by odds ratios (ORs) and 95% confidence intervals.Results:The multivariate analysis showed that maternal BMI (normal/underweight OR: 0.23, overweight/underweight OR: 0.15, obese/underweight OR: 0.13) and maternal ethnicity (Fars/Sistani OR: 3.49) and maternal nutrition (good/poor OR: 0.46) were significantly correlated with NTDs in the newborns.Conclusions:This study showed that maternal ethnicity, insufficient nutrition, and BMI, were the main risk factors of NTDs in northern Iran.
    06/2014; 16(6):e7940. DOI:10.5812/ircmj.7940
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    • "The discovery that dietary folic acid supplementation before and during pregnancy can dramatically reduce the incidence of neural tube defects has been a major advance for child health12. However since the neural tube closes at day 27 during human gestation3, high levels of folic acid after this point may serve no benefit, and could even be detrimental4. "
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    ABSTRACT: Maternal folic acid supplementation is essential to reduce the risk of neural tube defects. We hypothesize that high levels of folic acid throughout gestation may produce neural networks more susceptible to seizure in offspring. We hence administered large doses of folic acid to rats before and during gestation and found their offspring had a 42% decrease in their seizure threshold. In vitro, acute application of folic acid or its metabolite 4Hfolate to neurons induced hyper-excitability and bursting. Cultured neuronal networks which develop in the presence of a low concentration (50 nM) of 4Hfolate had reduced capacity to stabilize their network dynamics after a burst of high-frequency activity, and an increase in the frequency of mEPSCs. Networks reared in the presence of the folic acid metabolite 5M4Hfolate developed a spontaneous, distinctive bursting pattern, and both metabolites produced an increase in synaptic density.
    Scientific Reports 03/2013; 3:1465. DOI:10.1038/srep01465 · 5.58 Impact Factor
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