Background/Objectives: 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) C677T and A1298C polymorphisms, alongside methionine synthase reductase (MTRR) A66G polymorphism and the methionine synthase (MTR) A2756G polymorphism) and serum folate levels as well as cognitive levels in Chinese preschoolers aged 5–7 years. Methods: 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 A1298C and C677T, together with MTRR A66G, were identified by Kramer’s Allele-Specific PCR (KASP) technique. The cognitive scores of children were assessed by questionnaire. Results: MTHFR 677TT and MTR 2756AG + GG correlated negatively with serum folate levels (TT vs. CC + CT, p = 0.0009 and AG + GG vs. AA, p = 0.0057, respectively). MTHFR C677T and A1298C were independently linked to an elevated risk of suboptimal cognitive development (TT vs. CC + CT, p = 0.0009 and AA vs. CA + CC, p < 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 (p < 0.05). Conclusions: 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.

Background/Objectives: Adults at high risk of type 2 diabetes frequently show concurrent dyslipidemia, insulin resistance, and central adiposity before overt diabetes develops. We evaluated cardiometabolic responses to standardized whole-grain staple replacement and examined grain-quality patterns in free-living and country-level settings. Methods: This secondary exploratory analysis included 144 participants (48 per group) from a 12-week, three-arm randomized dietary trial. Participants were analyzed according to their randomized assignments to 100 g/day, 50 g/day, or control. Lipid, anthropometric, body composition, and composite cardiometabolic phenotypes were evaluated. Longitudinal and time-weighted cumulative effects were estimated using linear mixed-effects and regression models, with Benjamini–Hochberg false discovery rate (FDR) correction applied within the corresponding multiplicity domains. Complementary analyses included 30,769 NHANES adults without diabetes, including 12,169 with prediabetes, and descriptive country-level data on whole-grain intake, high-FPG-attributable diabetes burden, and cereal supply. Results: Within the extended phenotype panel, HWG versus control time-weighted cumulative effects included triglycerides (β = −0.220, 95% CI −0.397 to −0.043; FDR-adjusted p = 0.047), the atherogenic index of plasma (β = −0.125, −0.191 to −0.060; FDR-adjusted p = 0.002), and the triglyceride–glucose index (β = −0.301, −0.429 to −0.173; FDR-adjusted p < 0.001). Conventional lipid components showed distinct temporal responses. In NHANES, higher whole-grain exposure and more favorable grain-quality ratios were associated with lower adiposity- and insulin resistance-related phenotypes, whereas refined-grain exposure generally showed the opposite pattern. Country-level analyses showed marked heterogeneity in whole-grain intake, diabetes burden, and cereal supply context. Conclusions: Standardized whole-grain staple replacement was associated with short-term changes across several cardiometabolic dimensions in adults at high risk of type 2 diabetes, with the clearest extended-phenotype signals involving triglyceride-related and glucose–triglyceride coupling measures. NHANES identified cross-sectional grain-quality associations in free-living adults; country-level analyses described heterogeneity in whole-grain intake, diabetes burden, and cereal supply context.