This study was designed to investigate whether the risk for neural tube defects (NTDs) was associated with reduced folate carrier gene (RFC1 A80G) polymorphism and/or with the interaction between the RFC1 gene and maternal periconceptional use of folic acid. One hundred four nuclear families with NTDs and 100 non-malformed control families were sampled to investigate the potential interaction between maternal or the offspring's RFC1 (A80G) genotypes and the maternal periconceptional use of folic acid through a population-based case-control study. RFC1 (A80G) genotypes were detected using PCR-restricted fragment length polymorphism (PCR-RFLP). Mother who had the GG genotype and did not take folic acid had an elevated risk for NTDs (OR = 5.43, 95% CI = 1.68-18.28) as compared to the mother who had AA or GA genotype and took maternal periconceptional folic acid. The interactive coefficient was 1.12 between maternal GG genotype and the periconceptional folic acid non-use. The risk for having an infant with NTDs was 8.80 (95% CI = 2.83-28.69) for offspring with the GG genotype, as compared to the offspring with AA or GA genotype among the mothers who did not take folic acid supplements. The interactive coefficient was 1.45 for offspring with the GG genotype and without maternal periconceptional supplementation of folic acid. Our findings suggest that there is a potential gene-environment interaction on the risk of NTDs between maternal or offspring RFC1 GG genotype and maternal periconceptional intake of folic acid. The RFC1 is likely to be an important candidate gene in folate transportation and RFC1 GG genotype (A80G) may be associated with an increased risk for NTDs in this Chinese population.
"However, only the rs3788200 located in intron 2 and the rs1888530 SNP located in intron 5 were found to be significantly associated with MM. Although neither of these SNPs have been previously evaluated for MM risk, a nonsynonymous variant in exon 2 (rs1051266) has shown association with NTD risk in three other studies of two population groups (Shang et al., 2008; Franke et al., 2009; Pei et al., 2009). It is important to note that the mouse knockout for the SLC19A1 gene is embryonic lethal. "
[Show abstract][Hide abstract] ABSTRACT: Meningomyelocele (MM) results from lack of closure of the neural tube during embryologic development. Periconceptional folic acid supplementation is a modifier of MM risk in humans, leading toan interest in the folate transport genes as potential candidates for association to MM.
This study used the SNPlex Genotyping (ABI, Foster City, CA) platform to genotype 20 single polymorphic variants across the folate receptor genes (FOLR1, FOLR2, FOLR3) and the folate carrier gene (SLC19A1) to assess their association to MM. The study population included 329 trio and 281 duo families. Only cases with MM were included. Genetic association was assessed using the transmission disequilibrium test in PLINK.
A variant in the FOLR2 gene (rs13908), three linked variants in the FOLR3 gene (rs7925545, rs7926875, rs7926987), and two variants in the SLC19A1 gene (rs1888530 and rs3788200) were statistically significant for association to MM in our population.
This study involved the analyses of selected single nucleotide polymorphisms across the folate receptor genes and the folate carrier gene in a large population sample. It provided evidence that the rare alleles of specific single nucleotide polymorphisms within these genes appear to be statistically significant for association to MM in the patient population that was tested.
Birth Defects Research Part A Clinical and Molecular Teratology 08/2010; 88(8):689-94. DOI:10.1002/bdra.20706 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neural tube defects (NTDs) are common, severe congenital malformations whose causation involves multiple genes and environmental factors. Although more than 200 genes are known to cause NTDs in mice, there has been rather limited progress in delineating the molecular basis underlying most human NTDs. Numerous genetic studies have been carried out to investigate candidate genes in cohorts of patients, with particular reference to those that participate in folate one-carbon metabolism. Although the homocysteine remethylation gene MTHFR has emerged as a risk factor in some human populations, few other consistent findings have resulted from this approach. Similarly, attention focused on the human homologues of mouse NTD genes has contributed only limited positive findings to date, although an emerging association between genes of the non-canonical Wnt (planar cell polarity) pathway and NTDs provides candidates for future studies. Priorities for the next phase of this research include: (i) larger studies that are sufficiently powered to detect significant associations with relatively minor risk factors; (ii) analysis of multiple candidate genes in groups of well-genotyped individuals to detect possible gene-gene interactions; (iii) use of high throughput genomic technology to evaluate the role of copy number variants and to detect 'private' and regulatory mutations, neither of which have been studied to date; (iv) detailed analysis of patient samples stratified by phenotype to enable, for example, hypothesis-driven testing of candidates genes in groups of NTDs with specific defects of folate metabolism, or in groups of fetuses with well-defined phenotypes such as craniorachischisis.
Human Molecular Genetics 10/2009; 18(R2):R113-29. DOI:10.1093/hmg/ddp347 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The worldwide incidence of neural tube defects (NTDs) ranges from 1.0 to 10.0 per 1,000 births with almost equal frequencies between two major categories: anencephaly and spina bifida (SB). Epidemiological studies have provided valuable insight for (a) researchers to identify nongenetic and genetic factors contributing to etiology, (b) public health officials to design and implement policies to prevent NTD pregnancies, and (c) individuals to take precautions to reduce the chance of having an NTD-affected pregnancy. Despite extensive research, our knowledge of the genetic etiology of human NTDs is limited. Although more than 200 small animal models with NTDs exist, most of these models do not replicate the human disease phenotype. Over a hundred candidate genes have been examined for risk association to human SB. The candidate genes studied include those important in folic acid metabolism, glucose metabolism, retinoid metabolism, and apoptosis. Many genes that regulate transcription in early embryogenesis and maintain planar cell polarity have also been tested as candidates. Additionally, genes identified through mouse models of NTDs have been explored as candidates. We do not know how many genes in the human genome may confer risk for NTDs in human. Less than 20% of the studied candidate genes have been determined to confer even a minor effect on risk association. Many studies have provided conflicting conclusions due to limitations in study design that potentially affect the power of statistical analysis. Future directions such as genomewide association studies (GWAS) and whole exome or even whole genome sequencing are discussed as possible avenues to identify genes that affect risk for human NTDs.
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