Association between<i>MTHFD1</i> gene G1958A polymorphism and susceptibility to neural tube defects: a meta-analysis _Chinese Journal of Evidence-Based Medicine

Authors：

FANG Yulian ¹ , ZHANG Ruiping ² , ZHI Xiufang ² , CAO Lirong ² , WANG Yizheng ² ,  CAI Chunquan ³

1. Institute of Pediatric, Tianjin Children’s Hospital, Tianjin, 300134, P.R.China;
2. Graduate College of Tianjin Medical University, Tianjin, 300070, P.R.China;
3. Department of Neurosurgery, Tianjin Children’s Hospital, Tianjin, 300134, P.R.China;

Corresponding author：

CAI Chunquan, Email: tjpns@126.com

Keywords：

neural tube defects; methylenetetrahydrofolate dehydrogenase; gene polymorphism; meta-analysis

DOI：

10.7507/1672-2531.201612098

Video：

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Objective To evaluate associations betweenMTHFD1 gene G1958A polymorphism and the risk of neural tube defects (NTDs). Methods We electronically searched databases including PubMed, The Cochrane Library, Web of Science, CNKI, VIP, and WanFang Data from inception to June 2016 to collect case-control studies of the correlation between the G1958A polymorphism inMTHFD1 and the risk of NTDs. Two reviewers independently screened the studies, extracted data and assessed the risk of bias of included studies, and then, meta-analysis was performed using Stata 12.0 software. Results Thirteen case-control studies were included, involving 1 724 NTDs infants, 1 485 mothers and 774 fathers with NTDs offspring. The results of meta-analysis showed that there was significant association betweenMTHFD1 gene G1958A polymorphism and increased risk of NTDs in infants (AAvs. GG: OR=1.437, 95%CI 1.100 to 1.878,P=0.008; AA+AGvs. GG: OR=1.187, 95%CI 1.031 to 1.367,P=0.017; Avs. G: OR=1.210, 95%CI 1.050 to 1.394,P=0.008). However, there was no association between biparentalMTHFD1 gene G1958A polymorphism and NTDs in the offspring. Conclusion The current evidence shows thatMTHFD1 gene G1958A polymorphism may be a genetic risk factor for NTDs. Due to the limited quantity and quality of the included studies, more high quality studies are needed to verify the above conclusion.

Citation： FANG Yulian, ZHANG Ruiping, ZHI Xiufang, CAO Lirong, WANG Yizheng, CAI Chunquan. Association betweenMTHFD1 gene G1958A polymorphism and susceptibility to neural tube defects: a meta-analysis . Chinese Journal of Evidence-Based Medicine, 2017, 17(4): 395-401. doi: 10.7507/1672-2531.201612098 Copy

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8.	Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analysis. Eur J Epidemiol, 2010, 25(9): 603-605.
9.	Brody LC, Conley M, Cox C,et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet, 2002, 71(5): 1207-1215.
10.	Parle-McDermott A, Kirke PN, Mills JL,et al. Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet, 2006, 14(6): 768-772.
11.	Carroll N, Pangilinan F, Molloy AM,et al. Analysis of the MTHFD1 promoter and risk of neural tube defects. Hum Genet, 2009, 125(3): 247-256.
12.	Doudney K, Grinham J, Whittaker J,et al. Evaluation of folate metabolism gene polymorphisms as risk factors for open and closed neural tube defects. Am J Med Genet A, 2009, 149A (7): 1585-1589.
13.	Marini NJ, Hoffmann TJ, Lammer EJ,et al. A genetic signature of spina bifida risk from pathway-informed comprehensive gene-variant analysis. PLoS One, 2011, 6(11): e28408.
14.	Meng J, Han L, Zhuang B. Association between MTHFD1 polymorphisms and neural tube defect susceptibility. J Neurol Sci, 2015, 348(1-2): 188-194.
15.	Hum DW, Bell AW, Rozen R,et al. Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase. J Biol Chem, 1988, 263(31): 15946-15950.
16.	Christensen KE, Rohlicek CV, Andelfinger GU,et al. The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Hum Mutat, 2009, 30(2): 212-220.
17.	Jiang J, Zhang Y, Wei L,et al. Association between MTHFD1 G1958A polymorphism and neural tube defects susceptibility: a meta-analysis. PLoS One, 2014, 9(6): e101169.
18.	Zheng J, Lu X, Liu H,et al. MTHFD1 polymorphism as maternal risk for neural tube defects: a meta-analysis. Neurol Sci, 2015, 36(4): 607-616.

1. Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet, 2003, 4(10): 784-793.
2. Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism with special refefences to cardiovascular disease and neural tube defects. J Inherit Metah Dis, 2011, 34(1): 75-81.
3. Berry RJ, Li Z, Erickson JD,et al. Prevention of neural tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med, 1999, 341(20): 1485-1490.
4. De Marco P, Merello E, Calevo MG,et al. Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk. J Hum Genet, 2006, 51(2): 98-103.
5. Prasoona KR, Sunitha T, Srinadh B,et al. Paternal transmission of MTHFD1 G1958A variant predisposes to neural tube defects in the offspring. Dev Med Child Neurol, 2016, 58(6): 625-631.
6. Hol FA, van der Put NM, Geurds MP,et al. Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahy- drofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin Genet, 1998, 52(2): 119-125.
7. van der Linden IJ, Heil SG, Kouwenberg IC,et al. The methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G>A variant is not associated with spina bifida risk in the Dutch population. Clin Genet, 2007, 72(6): 599-600.
8. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analysis. Eur J Epidemiol, 2010, 25(9): 603-605.
9. Brody LC, Conley M, Cox C,et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet, 2002, 71(5): 1207-1215.
10. Parle-McDermott A, Kirke PN, Mills JL,et al. Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet, 2006, 14(6): 768-772.
11. Carroll N, Pangilinan F, Molloy AM,et al. Analysis of the MTHFD1 promoter and risk of neural tube defects. Hum Genet, 2009, 125(3): 247-256.
12. Doudney K, Grinham J, Whittaker J,et al. Evaluation of folate metabolism gene polymorphisms as risk factors for open and closed neural tube defects. Am J Med Genet A, 2009, 149A (7): 1585-1589.
13. Marini NJ, Hoffmann TJ, Lammer EJ,et al. A genetic signature of spina bifida risk from pathway-informed comprehensive gene-variant analysis. PLoS One, 2011, 6(11): e28408.
14. Meng J, Han L, Zhuang B. Association between MTHFD1 polymorphisms and neural tube defect susceptibility. J Neurol Sci, 2015, 348(1-2): 188-194.
15. Hum DW, Bell AW, Rozen R,et al. Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase. J Biol Chem, 1988, 263(31): 15946-15950.
16. Christensen KE, Rohlicek CV, Andelfinger GU,et al. The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Hum Mutat, 2009, 30(2): 212-220.
17. Jiang J, Zhang Y, Wei L,et al. Association between MTHFD1 G1958A polymorphism and neural tube defects susceptibility: a meta-analysis. PLoS One, 2014, 9(6): e101169.
18. Zheng J, Lu X, Liu H,et al. MTHFD1 polymorphism as maternal risk for neural tube defects: a meta-analysis. Neurol Sci, 2015, 36(4): 607-616.

Chinese Journal of Evidence-Based Medicine

Association betweenMTHFD1 gene G1958A polymorphism and susceptibility to neural tube defects: a meta-analysis

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