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.
What this study found
Overall, blood folate showed an additive genotype pattern of CC > CT > TT when measured by microbiologic assay. Protein-based assays showed a different or reverse pattern, indicating that assay choice materially changed the observed association. The review included 40 eligible studies, with 38 in meta-analyses, and found that cross-assay comparability was limited. The authors concluded that blood folate assay methods should be standardized and that protein-based assays should be interpreted cautiously in this genetic context.
- Study & population
- Systematic review and meta-analysis of 40 eligible studies in nonpregnant, nonlactating healthy women aged 12-49 years from multiple countries.
- Intervention
- Across included studies, participants received either natural food folate or folic acid-containing supplements, with daily folate doses ranging from 115 mg DFEs to 6800 mg DFEs over 1 day to 6 months.
- Key limitation
- Evidence was highly heterogeneous in design, folate exposure, duration, and assay method, and most studies used protein-based assays rather than microbiologic assays.
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Open PDFOriginal abstract
BACKGROUND The methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism is a risk factor for neural tube defects. The T allele produces an enzyme with reduced folate-processing capacity, which has been associated with lower blood folate concentrations. OBJECTIVE We assessed the association between MTHFR C677T genotypes and blood folate concentrations among healthy women aged 12-49 y. DESIGN We conducted a systematic review of the literature published from January 1992 to March 2014 to identify trials and observational studies that reported serum, plasma, or red blood cell (RBC) folate concentrations and MTHFR C677T genotype. We conducted a meta-analysis for estimates of percentage differences in blood folate concentrations between genotypes. RESULTS Forty studies met the inclusion criteria. Of the 6 studies that used the microbiologic assay (MA) to measure serum or plasma (S/P) and RBC folate concentrations, the percentage difference between genotypes showed a clear pattern of CC > CT > TT. The percentage difference was greatest for CC > TT [S/P: 13%; 95% credible interval (CrI): 7%, 18%; RBC: 16%; 95% CrI: 12%, 20%] followed by CC > CT (S/P: 7%; 95% CrI: 1%, 12%; RBC: 8%; 95% CrI: 4%, 12%) and CT > TT (S/P: 6%; 95% CrI: 1%, 11%; RBC: 9%; 95% CrI: 5%, 13%). S/P folate concentrations measured by using protein-binding assays (PBAs) also showed this pattern but to a greater extent (e.g., CC > TT: 20%; 95% CrI: 17%, 22%). In contrast, RBC folate concentrations measured by using PBAs did not show the same pattern and are presented in the Supplemental Material only. CONCLUSIONS Meta-analysis results (limited to the MA, the recommended population assessment method) indicated a consistent percentage difference in S/P and RBC folate concentrations across MTHFR C677T genotypes. Lower blood folate concentrations associated with this polymorphism could have implications for a population-level risk of neural tube defects.