Neural Tube Defects and Folate Pathway Genes_ Family-Based Association Tests of Gene–Gene and Gene.pdfVIP

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 myelomeningo- cele. NTDs are the most common debilitating birth defect. Familial studies indicate a signifi- cant 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 devel- opment 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 essen- tial for the synthesis of DNA, cell division, tis- sue growth, and DNA methylation (Morrison et al. 1998). Methylation enables proper gene expression and chromosome structure mainte- nance, both of which are critical in the devel- oping 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 pericon- ceptional folate supplementation protects against congenital defects in the face, neural tube, and conotruncal region of the heart. Low folate could directly limit its availability to cells or indirectly disrupt methionine metabolism, thereby increasing homocysteine in the mater- nal serum (Rosenquist and Finnell 2001). Either mechanism implicates folate