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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: 7.03). 11/2006; 114(10):1547-52. DOI: 10.1289/ehp.9166
Source: PubMed

ABSTRACT 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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    • "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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    • "BHMT c.716G>A was found not to be related to plasma tHcy concentration (Fredriksen et al. 2007; Heil et al. 2000; Morin et al. 2003; Weisberg et al. 2003), but a recent large epidemiological study demonstrated decrease in dimethylglycine (the product of the BHMT reaction) according to the number of c.716A alleles (Fredriksen et al. 2007), suggesting that this polymorphism may have metabolic effects. The variant c.716A allele has been associated with increased risk (Morin et al. 2003), decreased risk (Boyles et al. 2006), or no change in risk (Zhu et al. 2005) of spina bifida, and decreased risk of coronary artery disease (Weisberg et al. 2003) and no association with risk of cardiovascular disease (Heil et al. 2000) or aortic aneurysm (Giusti et al. 2008). Furthermore, carriers of the variant allele have been reported to have increased risk of colorectal cancer (Koushik et al. 2006) and possibly decreased risk of colorectal adenoma when combined with high methyl status (Hazra et al. 2007). "
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