Methyl Donor Nutrient Intake as a Modulator of the Association between FTO Gene Variants and BMI: A Systematic Review with Meta-Analysis and Meta-Regression.

CONTEXT: Genetic variants in the fat mass and obesity-associated gene (FTO) are consistently associated with obesity risk across populations. Methyl donor (MetD) nutrients, including vitamins B2, B6, B9, B12, choline, betaine, and methionine, participate in epigenetic mechanisms and may modulate gene expression related to obesity susceptibility. OBJECTIVE: Whether MetD intake influences the association between FTO variants and body mass index (BMI) was evaluated in this systematic review and meta-analysis. DATA SOURCES AND EXTRACTION: A systematic search was conducted in the PubMed, Embase, Scopus, Web of Science, and Cochrane databases up to May 2025, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Seven studies, comprising 1843 participants (67% women) aged 20-70 years, were included: 3 were cross-sectional studies, 3 were case-control studies, and 1 was a nonrandomized trial. The rs9939609 variant was analyzed in all studies, and 1 study examined additional FTO variants. None reported all MetD nutrients. DATA ANALYSIS: Random-effects models were applied to calculate pooled associations. Publication bias was examined using funnel plots and the Egger test. Meta-regression assessed whether MetD intake explained differences in mean BMI across genotypes. RESULTS: Individuals homozygous for the risk allele of FTO single nucleotide polymorphisms had significantly higher BMI compared with nonrisk carriers (standardized mean difference = -0.31; 95% CI, -0.53 to -0.09). Meta-regression indicated that higher amounts of vitamin B12 intake attenuated the association between the risk genotype and BMI (β = -.050; 95% CI, -0.084 to -0.017; P = .008). No heterogeneity was detected (I2 = 0.0%; P = .983). Between-study variability was fully explained (τ2 = 0; residual I2 = 0.0%; adjusted R2 = 100%). No evidence of publication bias was observed (P = .169). CONCLUSION: This review and meta-analysis provide initial evidence that vitamin B12 intake exceeding population-level recommendations may modulate the association between FTO variants and BMI. These findings highlight the role of nutrition in genetic susceptibility to obesity and underscore the need for studies designed to address the limitations identified in this review to confirm these results and inform personalized nutrition strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42024609752.