Polymorphisms in MTHFD1 Gene and Susceptibility to Neural Tube Defects: A Case-Control Study in a Chinese Han Population with Relatively Low Folate Levels.
BACKGROUND
The polymorphism of methylenetetrahydrofolate dehydrogenase (MTHFD1) has been reported as a risk factor for neural tube defects (NTDs). In the present study, we aimed to investigate whether the single-nucleotide polymorphisms (SNPs) of MTHFD1 gene are associated with NTDs in a Chinese population and to determine their mechanism of action.


METHODS
MTHFD1 gene was scanned in a total of 270 NTDs cases and 192 healthy controls by using next-generation sequencing (NGS) method. After quality control procedures, 208 selected SNP sites in MTHFD1 gene were enrolled for follow-up statistical association analyses. Functional analyses were also performed for significant SNPs through bioinformatics analysis. Folic acid levels of brain tissue in available NTDs cases and healthy controls (113 and 123, respectively) were measured. Statistical and bioinformatics analyses were performed to investigate the relationship between SNPs in MTHFD1 and susceptibility to NTDs.


RESULTS
Statistical analysis showed that 2 independent SNPs, rs1956545 and rs56811449, confer the risk of NTDs (P value=0.0195, OR (odds ratio)=1.41, 95% CI (confidence interval)=1.06-1.88; P value=0.0107, OR=0.56, 95% CI=0.36-0.87). The haplotype GGGG, which consists of 4 SNPs (rs2236225, rs2236224, rs1256146, and rs6573559), is also associated with risk of NTDs (P value=0.0438, OR=0.7180, 95% CI=0.5214-0.9888). The risk allele C of rs1956545 is also associated with decreased folic acid levels in the brain (P value=0.0222, standard beta=-0.2238, 95% CI=-0.4128 - -0.0349) according to analysis in the subset of NTDs cases and healthy controls. Bioinformatics analysis indicates that rs1956545 and rs56811449 are within ENCODE regulatory regions, the open chromatin regions of blastula Trophoblast cell line, and histone-marked region of brain astrocyte cell line.


CONCLUSIONS
The polymorphism of SNP loci rs1956545 and rs56811449 as well as a haplotype in MTHFD1 gene could serve as an indicator for the occurrence of NTDs in Chinese population and some specific genotypes of the loci may have lower risk of developing NTDs.
Section of Physiology and Biochemistry of Exercise, The Capital Institute of Physical Education of China, Beijing, China (mainland).
Jian
J
Wu
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China (mainland).
Yihua
Y
Bao
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China (mainland).
Xiaolin
X
Lu
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China (mainland).
Lihua
L
Wu
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China (mainland).
Ting
T
Zhang
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China (mainland).
Jin
J
Guo
Department of Neurology, Capital Institute of Pediatrics, Beijing, China (mainland).
Jian
J
Yang
D000483:Alleles; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002681:China; D019295:Computational Biology / Q000379:methods; D005333:Fetus / Q000473:pathology; D005492:Folic Acid / Q000737:chemistry; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D009436:Neural Tube Defects / Q000208:ethnology / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D012307:Risk Factors; D050497:Stillbirth
D015778:Minor Histocompatibility Antigens; D005492:Folic Acid; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)