Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

Abstract

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs.MethodsAn electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis.ResultsA significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR = 2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR = 1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR = 1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR = 1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls.ConclusionThe results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted.

Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations

“…The most well-studied polymorphism in MTHFR gene is the replacement of the nucleotide thymine by cytosine at position 677 (Ala222Val) (Frosst et al, 1995). This variant, which is relatively common in many populations worldwide, produces a form of methylenetetrahydrofolate reductase that reduces activity at higher temperatures, leading to lower levels of circulating folate (5-methyl-THF), an accumulation of 5, 10-methylene-THF, and increased plasma homocystein levels (Ma et al, 1997;Yan et al, 2012). The frequency of T allele varies in different ethnic population.…”

Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies

“…The prevalence of the MTHFR 677TT genotype varies across ethnic groups and regions, ranging from ,2% in West African and African American populations (8,9) to .35% in some populations such as the northern Chinese and individuals of Mexican descent (8)(9)(10). Meta-analyses reported that mothers or infants with the TT genotype have significantly greater odds of a neural tube defect-affected pregnancy than do those with the CC genotype (11)(12)(13).…”

“…Given the association of the TT genotype with decreased blood folate concentrations (15,16) and increased risk of neural tube defects (11,12,17), understanding the magnitude of the impact that the MTHFR 677C.T polymorphism may have on blood folate concentrations could be critical in assessing the population-level risk of neural tube defects. The objective of this systematic review was to assess the association between MTHFR genotype and blood folate concentrations among women of reproductive age (12-49 y) by applying Bayesian meta-analytic techniques to develop summary estimates of percentage differences between blood folate concentrations by genotype with the use of data from trials and observational studies.…”

New criteria for supplementation of selected micronutrients in the era of nutrigenetics and nutrigenomics

“…The MTHFR C677T polymorphism is associated with a reduction in the bioavailability of folate and folate metabolites and therefore subjects bearing this polymorphism mimic the stage of very low dietary folate intake (Bagley & Selhub, 1998). Many studies have demonstrated that MTHFR polymorphisms or low levels of folate are directly related to neural tube defects (Yan et al, 2012) and also have now been implicated in the pathogenesis of several diseases and disorders, including leukemia (Pereira et al, 2006;Silva et al, 2013), colorectal cancer (Jokic et al, 2011), cardiovascular disease (Chen et al, 2012), and other congenital abnormalities (Yin et al, 2012).…”