A unique methylation pattern co-segregates with neural tube defect statuses in Han Chinese pedigrees.

Neural tube defects (NTDs) are a complex trait associated with gene-environment interactions. Folic acid deficiency and planar cell polarity gene mutations account for some NTD cases; however, the etiology of NTDs is still little understood. In this study, in three Han Chinese NTD pedigrees (two with multiple affected children), with no information on folic acid deficiency or supplement, we examined genome-wide methylation profiles of each individual in these families. We further compared methylation status among cases and normal individuals within the pedigrees. A unique methylation pattern co-segregated with affected status: NTD cases had more hypermethylated than hypomethylated CpG islands; genes with different methylations clustered in pathways associated with epithelial-to-mesenchymal transition (ZEB2, SMAD6, and CDH23), folic acid/homocysteine metabolism (MTHFD1L), transcription/nuclear factors (HDAC4, HOXB7, SOX18), cell migration/motility/adhesion, insulin and cell growth, and neuron/axon development. Although the genetics of NTD are likely complex, epigenetic changes may concentrate in certain key pathways.

Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population.

Neural tube defects (NTDs) are the most common and severe malformations of the central nervous system. The association of single nucleotide polymorphisms (SNPs) of the Frizzled 3 (FZD3) and Frizzled 6 (FZD6) genes and NTDs in the Han population of northern China was principally studied. One synonymous SNP (rs2241802) in FZD3 gene and three nonsynonymous SNPs (rs827528, rs3808553 and rs12549394) in FZD6 gene were analyzed by polymerase chain reaction (PCR) and sequencing methods in 135 NTD patients and 135 normal controls. The allele, genotype and haplotype frequencies were calculated and analyzed to examine the relationship between FZD3/FZD6 SNPs and NTDs. Both T allele and TT genotype frequencies of the FZD6 rs3808553 loci in the NTDs group were significantly higher than those in the controls, and children with T allele and TT genotype were associated with increased NTDs risk (OR = 1.575, 95 % CI 1.112-2.230, P = 0.010 and OR = 2.811, 95 % CI 1.325-5.967, P = 0.023, respectively). There were no differences among different genotypes or alleles in other three SNPs. Haplotypes A-G-C and A-T-C in FZD6 were found associated with NTDs in the case-control study (OR = 0.560, 95 % CI 0.378-0.830, P = 0.004 and OR = 1.670, 95 % CI 1.126-2.475, P = 0.011, respectively). The rs3808553 of FZD6 is obviously associated with NTDs in Han population of northern China. The TT genotype may increase risk for NTDs.

Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway.

BACKGROUND: Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring. METHODS: We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones. RESULTS: There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271-13.258; OR = 3.333, 95%CI: 1.068-10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070-3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023-3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361-11.308). CONCLUSION: Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.