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.

Systematic review and meta-analysis of 40 eligible studies in nonpregnant, nonlactating healthy women aged 12-49 years from multiple countries. Included evidence came from 8 controlled feeding studies, 2 cohort studies, and 30 cross-sectional studies evaluating blood folate by MTHFR C677T genotype.

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. The review compared blood folate concentrations by MTHFR C677T genotype (CC, CT, TT) rather than testing one standardized regimen.

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.

Evidence was highly heterogeneous in design, folate exposure, duration, and assay method, and most studies used protein-based assays rather than microbiologic assays. Several studies lacked assay reporting, and the included trials were generally short and small, limiting causal interpretation and comparability across studies. Findings are also limited to nonpregnant, nonlactating women of reproductive age.