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Meta-Analysis
. 2013 Apr 4;8(4):e59570.
doi: 10.1371/journal.pone.0059570. Print 2013.

Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature

Ti Zhang  1 , Jiao Lou, Rong Zhong, Jing Wu, Li Zou, Yu Sun, Xuzai Lu, Li Liu, Xiaoping Miao, Guanglian Xiong
Affiliations
Meta-Analysis

Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature

Ti Zhang et al. PLoS One. .

Abstract

Background: Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996-2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association.

Methods and findings: We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons MTHFR C677T (42 studies; 4374 cases, 7232 controls), MTHFR A1298C (22 studies; 2602 cases, 4070 controls), MTR A2756G (9 studies; 843 cases, 1006 controls), MTRR A66G (8 studies; 703 cases, 1572 controls), and RFC-1 A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of MTHFR C677T (OR 1.23; 95%CI 1.07-1.42) and suggestive evidence of RFC-1 A80G (OR 1.55; 95%CI 1.24-1.92). However, we found no significant effects of MTHFR A1298C, MTR A2756G, MTRR A66G in risk of NTDs in dominant, recessive or in allelic models.

Conclusions: Our meta-analysis strongly suggested a significant association of the variant MTHFR C677T and a suggestive association of RFC-1 A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Simplified overview of folate metabolism pathway, highlighting enzymes with polymorphisms investigated in this study.
MTHFR, methylene tetrahydrofolate reductase; MTR, methionine synthase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; MTRR, methionine synthase reductase; THF, tetrahydrofolate. RFC, the reduced folate carrier.
Figure 2
Figure 2. Flow chart of the literature search.
Figure 3
Figure 3. Pooled frequencies of the MTHFR C677T alleles and MTHFR A1298C alleles in controls stratified by ethnicity.
Native A, Native America.
Figure 4
Figure 4. The overall forest plot of OR with 95%CI for MTR A2756G, MTRR A66G and RFC-1 A80G polymorphism and Neural tube defects risk in dominant model.
Figure 5
Figure 5. The cumulative forest plot of OR with 95%CI for MTHFR C677T polymorphism, MTHFR A1298C and Neural tube defects risk in dominant model.
Figure 6
Figure 6. The funnel plot of natural logarithm of OR against inverse standard error in each study.
See this image and copyright information in PMC

References

    1. Christianson A (2006) Global Report on Birth Defects. March of Dimes Birth Defects Foundation.
    1. Pitkin RM (2007) Folate and neural tube defects. Am J Clin Nutr 85: 285S–288S. - PubMed
    1. Copp AJ, Greene ND, Murdoch JN (2003) The genetic basis of mammalian neurulation. Nat Rev Genet 4: 784–793. - PubMed
    1. Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, et al. (2005) Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicol Teratol 27: 515–524. - PMC - PubMed
    1. Smithells RW, Sheppard S, Schorah CJ (1976) Vitamin dificiencies and neural tube defects. Arch Dis Child 51: 944–950. - PMC - PubMed

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