From Genes to Surgery: How NOS3 Intron 4 Shapes Obesity Risk and Metabolic Outcomes ^†

Introduction: Obesity is a multifactorial disease with high global prevalence and substantial metabolic–cardiovascular burden. The NOS3 gene encodes endothelial nitric oxide synthase, which influences vascular tone and lipid regulation. This study investigated the association between the NOS3 intron 4 VNTR and morbid obesity in women aged ≥ 50 undergoing bariatric surgery, and it explored genotype-related clinical and metabolic traits. Methodology: We genotyped NOS3 intron 4 VNTR in 22 bariatric female patients (61.6 ± 5.0 years) undergoing Roux-en-Y gastric bypass and 81 controls (43 women, 38 men; 52 ± 5 years). Clinical, biochemical, and body-composition data were collected only in the bariatric group (Approved by the Research Ethics Committee (CEP) of the State Secretariat of Health of the Federal District (SES-DF) (FEPECS) under opinion number 1.910.166). Statistical analyses used Pearson’s chi-square and Mann–Whitney U tests (p < 0.05). Results: Compared with controls (Hardy–Weinberg equilibrium p = 0.760), the bb genotype was less frequent in cases (40.9% vs. 67.9%; p = 0.021), suggesting a protective effect (OR = 0.33; 95% CI 0.12–0.86). Conversely, the a allele was enriched in cases (47.7% vs. 17.9%) and conferred higher risk (OR = 4.19; 95% CI 2.05–8.56; p < 0.001). Within the bariatric group, ab displayed a more favorable metabolic profile—higher median vitamin B12 (927.00 pg/mL), total T4 (12.95 μg/dL), and lean mass (44,564 g). In contrast, aa was associated with retinopathy (50%; p = 0.048) and difficulty in chewing dry foods (80%; p = 0.029), indicating functional differences. Conclusion: The NOS3 intron 4 VNTR exhibits clinically meaningful associations in older women with morbid obesity. Specifically, the bb genotype appears protective, while the a allele increases risk. Furthermore, genotype-related metabolic and functional patterns in bariatric patients support incorporating genetic data into personalized obesity management.