Vitamin D genetic polymorphisms, adiposity, and hormonal response to a precision supplementation and genotype-guided diet intervention

Introduction: Background: vitamin D deficiency is highly prevalent in individuals with overweight or obesity, due to volumetric dilution and impaired metabolic activation. Genetic polymorphisms in VDR, CYP2R1, and GC genes may further influence serum 25-hydroxyvitamin D [25(OH)D] levels and responsiveness to supplementation. Objective: this study evaluated the longitudinal response to a 6-month, genotype-informed vitamin D₃ and nutritional intervention, and its impact on 25(OH)D, parathyroid hormone (PTH), insulin resistance (HOMA-IR), and inflammatory markers (hs-CRP), in a cohort stratified by BMI and vitamin D-related SNPs. Methods: a total of 116 adults (aged 18-50 years) were genotyped for VDR rs731236, CYP2R1 rs10741657, and GC rs2282679. Participants received personalized vitamin D₃ dosing (1000-6000 IU/day) and nutritional plans adjusted for genotype and BMI. Clinical parameters were measured at baseline (T0), 3 months (T1), and 6 months (T2). Genetic risk scores (GRS) were calculated, and ROC analysis assessed predictors of vitamin D sufficiency (25(OH)D ≥ 30 ng/mL). Results: serum 25(OH)D increased significantly from T0 to T2 (mean: 20.84 ± 4.55 to 37.64 ± 6.48 ng/mL, p < 0.001), alongside reductions in BMI, PTH, HOMA-IR, and hs-CRP (all p < 0.001). GC rs2282679 CC and CYP2R1 GG genotypes were associated with persistently lower 25(OH)D levels. Baseline 25(OH)D was the strongest predictor (AUC = 0.83). No significant BMI × genotype interaction was found. Conclusion: genotype-informed vitamin D₃ supplementation with lifestyle intervention improves endocrine and metabolic markers. Personalization based on key polymorphisms supports precision nutrition strategies in at-risk populations.