Neural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene-Gene and Gene-Environment Interactions
Boyles, Abee L., Billups, Ashley V., Deak, Kristen L., Siegel, Deborah G., Mehltretter, Lorraine, Slifer, Susan H., Bassuk, Alexander G., Kessler, John A., Reed, Michael C., Nijhout, H. Frederik, George, Timothy M., Enterline, David S., Gilbert, John R., Speer, Marcy C., Environmental Health Perspectives
BACKGROUND: 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.
OBJECTIVES: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation.
METHODS: 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 hydroxymethyltransferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase.
RESULTS: 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.
CONCLUSIONS: 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.
KEY WORDS: folate, folic acid supplementation, genetic association, neural tube defects. Environ Health Perspect 114:1547-1552 (2006). doi:10.1289/ehp.9166 available via http://dx.doi.org/[Online 15 June 2006]
Of 1,000 births worldwide, in one embryo the neural tube will fail to close properly 28 days after conception, resulting in some form of neural tube defect (NTD). Failed closure at the cranial end, known as anencephaly, is a lethal condition, whereas failed closure at the caudal end usually results in a myelomeningocele. NTDs are the most common debilitating birth defect. Familial studies indicate a significant genetic component to NTDs, with a 40-fold increase in risk in first-degree relatives (Elwood et al. 1992). Myriad environmental exposures have been implicated in the development of NTDs; most notably, a significant decrease in risk can be achieved by maternal folic acid supplementation before conception.
The mechanism by which dietary folate supplementation prevents NTDs is poorly understood (MRC Vitamin Study Research Group 1991). Folic acid derivatives are essential for the synthesis of DNA, cell division, tissue growth, and DNA methylation (Morrison et al. 1998). Methylation enables proper gene expression and chromosome structure maintenance, both of which are critical in the developing embryo (Razin and Kantor 2005). The folate and methionine cycles are linked by the conversion of homocysteine to methionine (Figure 1). In the absence of food frequency data, maternal vitamin supplementation can also serve as a proxy for overall health because of the positive correlation between supplement intake, diet, and a healthy lifestyle (Slesinski et al. 1996). Vitamin supplementation is an important cofactor to consider when studying nutritionally related genes.
Animal models demonstrate that periconceptional folate supplementation protects against congenital defects in the face, neural tube, and conotruncal region of the heart. …