Abstract
Objective: Neural tube defect (NTD) incidence could be effectively reduced by folic acid supplementation before and during pregnancy. We studied single nucleotide polymorphisms (SNPs) involved in folate metabolism to explore genetic susceptibility to NTD. We studied the association between 12 SNPs involved in 11 folate metabolism genes and NTDs. Methods: We enrolled 76 children with NTD and 188 control children. We genotyped 12 folate metabolism SNPs including CBS-C699T, DHFR-c594+59del19, GSTO1-C428T, MTHFD-G1958A, MTHFR-C677T, MTHFR-A1298C, MTR-A2756G, MTRR-A66G, NFE2L2-ins1+C11108T, RFC1-G80A, TCN2-C776T, and TYMS-1494del6 using SNaPShot genotyping technology and confirmed by Sanger sequencing. Results: One SNP, TYMS-1494del6, and one compound wide-type genotype of RFC1-G80A, MTHFR-A1298C and TCN2-C776T might decrease NTD risk, and three compound mutation genotypes of MTHFD-G1958A, MTHFRC677T, and MTR-A2756G; MTHFD-G1958A, MTR-A2756G, and RFC1-G80A; and RFC1-G80A, MTHFR-A1298C, and TCN2-C776T might increase NTD risk. The TT genotype of TYMS-1494del6 (P<0.001) and the AT+TT genotype of TYMS-1494del6 (P=0.009) were significant genotypes. Fourteen in 188 control babies carried the compound wide-type genotype of RFC1-G80A, MTHFR-A1298C, and TCN2-C776T, but none in 76 NTD babies (P=0.014). The ratios of the two compound mutants for MTHFD-G1958A, MTHFR-C677T, MTR-A2756G, and MTHFD-G1958A, RFC1-G80A, MTR-A2756G in NTD were higher than in control babies (P=0.021) and RFC1- G80A, MTHFR-A1298C, and TCN2-C776T (P=0.029). Conclusions: The TT genotype of TYMS-1494del6 and the two wide-type genotypes of RFC1-G80A, MTHFRA1298C, and TCN2-C776T are protective in NTD. Three compound mutation genotypes of MTHFD-G1958A, MTHFR-C677T, MTR-A2756G, MTHFD-G1958A, MTR-A2756G, RFC1-G80A, and RFC1-G80A, MTHFR-A1298C, TCN2-C776T might increase susceptibility to NTD.
Highlights
Neural tube defects (NTDs) are a group of serious birth defects that affect the developing nervous system and include anencephaly, spina bifida, and encephalocele [1]
The resulting OR for NTDs carrying the TT homozygous genotype of TYMS-1494del6 compared to the control group was 0.24, 95% CI = [0.11- 0.54], P
The resulting OR for NTDs carrying the AT+TT genotype of TYMS-1494del6 compared to the control group was 0.39, 95% CI = [0.19 - 0.80], P=0.009
Summary
Neural tube defects (NTDs) are a group of serious birth defects that affect the developing nervous system and include anencephaly, spina bifida, and encephalocele [1]. NTDs are the second most common of birth defects, which are preventable and are significant causes of infant death and childhood disability [1,2]. It is estimated that there are more than 300,000 NTDs worldwide each year, many of these occurring in low-resource countries [3]. And spina bifida are the most common NTDs and occur with about equal frequency, whereas encephalocele is seen less frequently. Spina bifida with meningomyelocele results from failure of the vertebral arches to close over an open neural tube defect, exposing the spinal cord and nerves [4].
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