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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Available from: Susan Slifer, Oct 09, 2015
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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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    • "In contrast, other studies have found either no association of 677C-T with increased risk of NTD (for example, Boyles et al., 2006; Dávalos et al., 2000; Erdogan et al., 2010; Johnson WE et al., 1999; Stegmann et al., 1999,) or even a protective effect (Doudney et al., 2009 and Relton et al., 2003) of the 677C-T polymorphism. Yet, other studies suggested that additional candidate genes other than MTHFR may be responsible for an increased risk to NTD in some American Caucasian families (Rampersaud et al., 2003). "
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    ABSTRACT: 1 report that 35·9% of the pregnancies were unplanned. This is an important statistic, the implications of which they do not explore. The figure concurs with findings from a 1997 Health Education Authority (HEA) survey of 299 pregnant women, 30% of whom had not planned their pregnancy. 2 One of the greatest challenges the HEA faces in the final year of its education campaign is to make all women of childbearing age aware of the importance of folic-acid supplementation by positioning it as a general women's health issue. In a recent HEA study, 95% of general practitioners knew that folic acid should be taken before conception, but only 42% gave this advice to women of childbearing age. 3 For more women to take supplements at the correct time, information about folic acid needs to reach them before they are planning to be pregnant. This is why the HEA is now calling on general practitioners, nurses, family-planning specialists, and other health professionals to broaden their approach to women by giving advice on folic acid as part of other related consultations, such as discussions about contraception or dietary advice. Women should be advised of the benefits of eating more foods rich in folic acid, particularly fortified foods such as breads and breakfast cereals. If this can be achieved, concentrations of this important B vitamin will be boosted before pregnancy. This would not only be of benefit to women whose pregnancies are unplanned, but also to those who have not taken supplements before conception. The HEA recently introduced a new folic-acid flash labelling scheme so that women can identify foods fortified with folic acid. The ideal is for all pregnancies to be planned, and for all women to take a daily 400 µg folic-acid supplement as
    Neural Tube Defects - Role of Folate, Prevention Strategies and Genetics, 03/2012; , ISBN: 978-953-51-0317-2
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