Maternal gene polymorphisms involved in folate metabolism and risk of Down syndrome offspring: a meta-analysis

Abstract

Studies investigating the association between gene polymorphisms involved in homocysteine/folate metabolism and Down syndrome (DS) have reported contradictory or inconclusive results. A meta-analysis of 11 case-control studies relating MTHFR C677T, MTHFR A1298C and MTRR A66G gene polymorphisms to the maternal risk of DS was carried out. For MTHFR C677T polymorphism the heterogeneity between studies was significant (P = 0.03) and the random effects (RE) pooled odds ratio (OR) was not significant: RE OR = 1.18 (0.99-1.40). The recessive model for allele MTHFR 677T showed nonsignificant heterogeneity overall (P = 0.21) and the association was not significant: fixed effects (FE) OR = 1.27 (0.98-1.64). However, sensitivity analysis changed the pattern of results and the association became marginally significant [FE OR = 1.31 (1.01-1.71)]. The dominant model showed no association. Finally, statistically significant associations between the MTHFR A1298C and MTRR A66G gene polymorphisms and the risk of DS were not found. The cumulative meta-analysis of MTHFR C677T showed a trend toward an association as the amount of data increased, and the recursive cumulative metaanalysis indicated that there was insufficient evidence for claiming or denying an association for all gene polymorphisms. In addition, there was no difference between the magnitude of effect observed in large versus small studies. Large and rigorous case-control studies that investigate gene-gene and gene-environment interactions need to be performed before conclusive claims about the genetics of DS can be made.

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome — meta-analysis

“…However, the article written in Portuguese was later published in English, and thus included [21]. One previous meta-analysis was found [22]. Our meta-analysis was performed only on the polymorphisms investigated in at least three studies.…”

Folate Pathway Gene MTHFR C677T Polymorphism and Risk of Lung Cancer in Asian Populations

“…Heterogeneity was quantified with the I 2 metric (I 2 =(Q-df)/Q), which is independent of the number of studies in the meta-analysis. I 2 takes values of between 0 and 100%, with higher values denoting a greater degree of heterogeneity (Zintzaras and Hadjigeorgiou 2005;Zintzaras and Ioannidis, 2005;Zintzaras, 2007). Random effects modeling assume a genuine diversity in the results of various studies, and it incorporates a between-study variance into the calculations.…”

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

“…The distribution of genotypes in the control groups were in Hardy-Weinberg equilibrium (HWE) in all studies. Lack of HWE indicates possible genotyping errors and/or population stratification (Zintzaras, 2007).…”

“…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.…”