Assessing the Association between the Methylenetetrahydrofolate Reductase (MTHFR) 677C->T Polymorphism on Blood Folate Concentrations: A Systematic Review and Meta-analysis of Trials and Observational Studies

Abstract

Objectives: The methylenetetrahydrofolate reductase (MTHFR) 677C->T polymorphism is a risk factor for neural tube birth defects (NTDs). The T allele produces an enzyme with reduced folate processing capacity, which has been shown to produce lower blood folate concentrations in some studies. Our objective was to assess the association between MTHFR C677T genotypes (CC, CT, TT) and blood folate concentrations among women aged 12-49 years. Methods: We conducted a systematic review of literature published between 1/1992-7/2013 to identify controlled trials and observational studies that reported serum, plasma, or red blood cell (RBC) folate concentrations and MTHFR C677T genotype. We applied a Bayesian random-effects model to predict differences in blood folate concentrations between MTHFR C677T genotypes, stratified by folate assay. Results: Thirty-eight studies met criteria for inclusion. Serum/plasma folate concentrations showed a consistent genotype trend with the highest concentrations for CC (CC > CT > TT) regardless of assay type. RBC folate concentrations measured by microbiologic assay also demonstrated this trend; however, this trend was reversed (CC < CT < TT) in studies using protein-binding assays. Conclusions: Meta-analyses results showed blood folate concentrations differed by assay type and genotype. Previous evidence has shown that RBC folate concentrations measured with a radioimmunoassay requires adjustment for genotype-dependent folate recovery; our results suggest that other protein-binding assays could have similar limitations. Compared to CC individuals, TT individuals have lower blood folate concentrations, which may increase a woman's risk for an NTD-affected pregnancy.