Gene-diet interactions between CETP, LPL, and LIPC genetic risk score and dietary fat and carbohydrate intake on lipid levels in Mexican adults

Objective To evaluate the interaction between dietary lipid and carbohydrate intake and a combined genetic risk score (uGRS) based on CETP, LPL, and LIPC variants in relation to HDLc, triglyceride, and total cholesterol concentrations in Mexican adults. Methods A cross-sectional study was conducted among adults from western Mexico recruited between June 2024 and May 2026. Dietary intake and fasting biochemical parameters were assessed using standardized procedures. Genotyping of CETP (rs708272), LPL (rs13702), and LIPC (rs1800588) was performed using TaqMan real-time PCR assays. Participants were classified according to an unweighted genetic risk score (uGRS) and grouped by the number of risk alleles. Linear regression models, analysis of covariance, and moderation analyses were used to examine gene–diet interactions between dietary fat and carbohydrate intake and lipid related metabolic outcomes. Approval was obtained from the Ethics (CEI-01-2025-08) and Biosafety (CBIO-01-2025-08) Committee of the University Center of Altos of the University of Guadalajara (CUALTOS-UdeG, Mexico). Results A total 234 individuals were included in the analysis; significant gene–diet interactions were observed between the combined genetic risk score and dietary macronutrient intake. Participants with higher genetic risk (4–6 risk alleles) who consumed < 30% of total energy from lipids exhibited higher total cholesterol concentrations (230.57 mg/dL) than those consuming > 30% of total energy from lipids (150.54 mg/dL; P = 0.045). Furthermore, participants carrying 4–6 risk alleles and consuming > 8% of total energy from polyunsaturated fatty acids (PUFAs) presented lower HDL-c concentrations (24.00 mg/dL) than those consuming < 8% of total energy from PUFAs (56.64 mg/dL; P = 0.044). In addition, participants with a lower genetic risk (0–2 risk alleles) and a higher carbohydrate intake showed lower triglyceride concentrations (89.36 mg/dL) compared with those with a moderate genetic risk (3–4 risk alleles) and a higher carbohydrate intake (130.06 mg/dL; P = 0.036). Conclusion The genetic risk by CETP, LPL, and LIPC variants may modulate the relationship between dietary fat and carbohydrate intake and lipid-related levels. The observed interactions suggest that individuals with different genetic profiles may exhibit distinct metabolic responses to dietary macronutrient intake, particularly regarding total cholesterol, triglyceride, and HDLc concentrations. In this context, the combination of these variants may help identify dietary patterns that are more favorable to specific genetic profiles, thereby supporting the development of nutrigenetic recommendations to improve lipid metabolism.