Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature

Abstract

BackgroundNeural 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 FindingsWe 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.ConclusionsOur 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.

Maternal methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and risk of nonsyndromic Cleft lip and/or Palate (NSCL/P) in offspring: A meta-analysis

“…34 Several meta-analysis studies illustrate the utility of the technique in identifying genes of small effects like MTHFR with phenotypes like -NTD, 35 Down syndrome, 36 Cardiovascular disease, 37 Migraine, 38 Schizophrenia, 39 bipolar disorder, 40 and depression. 41 The present meta-analysis (including 1019 case mothers and 16494 controls) was performed to assess the relationship between MTHFR A1298C polymorphism and NSCL/P with ten published case control studies, but no significant association was found in the total population.…”

Meta-analysis of methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism and risk of orofacial cleft

“…The association of MTHFR polymorphisms with the increased risk of OFC supports the protective effect of maternal use of multivitamins containing folic acid with respect to the occurrence of orofacial clefts (Bailey et al, 2005). Several meta-analysis studies illustrate the utility of the technique in identifying genes of small effects like MTHFR with phenotypes like-NTD (Zhang et al, 2013); down syndrome (Zintzaras, 2007;; cardiovascular disease (Xuan et al, 2011), stroke (Yadav et al, 2013); migraine (Shurks et al, 2010), Alzheimer's (Zhang et al, 2010), bipolar disorder (Rai, 2011), and depression (Zintzaras, 2006;. Author identified one meta-analysis (Verkleij-Hagoort et al, 2007) published in 2007 concerning similar topic during the literature search.…”

Methylenetetrahydrofolate reductase polymorphisms as possible risk factors of venous thrombosis – too weak to take care, too frequent to be ignored…

“…It has been demonstrated that MTHFR C677T SNP was associated with a significant risk of neural tube defects in the developing foetus, as well as repetitive miscarriages and cardiovascular disorders in adults [1,[21][22][23]. However, despite proven correlation between the above-mentioned risk of cardiovascular disorders and 677T allele prevalence, the contribution of this MTHFR variant to the increased risk of vein thrombosis remains equivocal.…”