Synergistic Effects of MTHFR, MTRR, and MTR Gene Variants on Serum Folate Levels and Cognitive Function in Chinese Preschoolers: A Cross-Sectional Study.

: Subnormal folate levels have a detrimental impact on the growth and development of preschoolers. We aimed to investigate the association between independent/synergistic effects of the gene polymorphisms (methyltetrahydrofolate reductase (MTHFR) and polymorphisms, alongside methionine synthase reductase (MTRR) polymorphism and the methionine synthase (MTR) polymorphism) and serum folate levels as well as cognitive levels in Chinese preschoolers aged 5-7 years. : Data were sourced from 614 children, acquired through the "Long-term Health Effects Assessment Project of Infants and Toddlers Nutritional Pack (LHEAITNP)" program were used. Folate serum concentrations were measured using a microbiologically modified technique. The genotypes of MTHFR and , together with MTRR , were identified by Kramer's Allele-Specific PCR (KASP) technique. The cognitive scores of children were assessed by questionnaire. : MTHFR and MTR correlated negatively with serum folate levels ( vs. , = 0.0009 and vs. , = 0.0057, respectively). MTHFR and were independently linked to an elevated risk of suboptimal cognitive development ( vs. , = 0.0009 and vs. , < 0.0001, respectively). The joint impact of these risk genotypes showed significantly increased risk of folate deficiency and inferior cognitive function compared to non-risk genotypes, particularly in those with more than two risk genotypes. The findings were corroborated by a cumulative effects model ( < 0.05). : Our results indicate the substantial association between folate-homocysteine metabolism gene variants and serum folate status/cognitive performance in Chinese preschoolers. Potential gene-nutrient interactions worthy of longitudinal investigation.