Sex-Specific Associations Between MTHFR, PPARG and ADRB3 Polymorphisms, Habitual Nutrient Intake and Metabolic Risk...

Background/Objectives: Genetic polymorphisms modulate the risk of metabolic complications of obesity; yet, it remains unclear how genotype reshapes actual dietary intake and why these mechanisms differ between men and women. The aim of this study was to identify sex-specific associations of three common polymorphisms (MTHFR C677T, PPARG Pro12Ala, ADRB3 Trp64Arg) with habitual nutrient intake in patients with obesity, and to explore candidate sex-differentiated dietary hypotheses for future prospective testing. Methods: A single-centre cross-sectional study was performed in 348 patients with obesity (83 men, 265 women; BMI ≥ 30 kg/m²; age 18-60 years). Genotyping was performed by allele-specific real-time PCR from buccal swabs. Habitual intake of more than 18 nutrients was assessed using a standardised Russian software-based questionnaire. Statistical analysis included Kruskal-Wallis and Mann-Whitney tests with Bonferroni correction (threshold p < 0.017), as well as odds ratios (OR) with 95% confidence intervals. Genotype distributions were tested for Hardy-Weinberg equilibrium, and genotype-nutrient associations were additionally examined in models adjusted for age, BMI and total energy intake. Results: Three genotype-phenotype associations remained significant after Bonferroni correction. In men, the dominant-heterozygous MTHFR C/T genotype was associated with a hypercaloric dietary pattern-excess protein, fat, sodium and phosphorus-and with a high risk of arterial hypertension (OR 5.96, 95% CI 1.48-24.08; p = 0.010). The sodium load in C/T carriers was a consequence of overall overeating rather than a selective preference for salty foods. In men, ADRB3 Trp64Arg carriage was associated with massive dietary cholesterol overconsumption (+466% vs. +153% in Trp/Trp; p = 0.012), whereas in women the opposite direction was observed. The PPARG G/G genotype in women was associated with elevated alanine aminotransferase (p = 0.027), most pronounced under 40 years (p = 0.011), and is considered a marker of hepatic risk without a confirmed dietary target. In women, the MTHFR T/T homozygous genotype showed suggestive associations with excessive mono-/disaccharide intake and a tendency toward hypertension (OR 2.62, 95% CI 1.07-6.43; p = 0.035); however, these did not survive FDR correction and require independent validation. Conclusions: Genetic polymorphisms were associated with sex-specific patterns of actual dietary intake, a finding that extends current knowledge beyond biochemical risk associations. Based on these associations, we propose testable hypotheses rather than clinical recommendations: that caloric restriction (with consequent sodium reduction) in men with MTHFR C/T, cholesterol restriction in men with ADRB3 Arg64, and mono-/disaccharide restriction in women with MTHFR T/T might reduce metabolic risk; women with PPARG G/G may warrant ALT monitoring. These findings suggest that genotype-informed dietary strategies may need to be sex-specific, and that the window for intervention may be earlier in life than currently practised. However, these hypotheses require prospective interventional validation before any clinical application.