FTO rs17817449 Variant Increases the Risk of Severe Obesity in a Brazilian Cohort: A Case-Control Study

Obesity is a complex disease caused by a combination of genetic, environmental, and epigenetic factors, and is associated with an increased risk of chronic diseases. The leptin-melanocortin pathway integrates peripheral signals about the body's energy stores with a central neuronal circuit in the hypothalamus. This pathway has been extensively studied over the years, as genetic variations in genes related to it may play a crucial role in determining an individual's susceptibility to obesity. Therefore, we analyzed the association between obesity and specific polymorphisms in leptin-melanocortin-related genes such as rs1137101, rs1042571, rs7799039, rs6265, rs17817449, rs121909065, and rs16147/rs5574. The study enrolled 501 participants from Rio de Janeiro, Brazil, with obesity class II or greater (BMI ≥ 35 kg/m2) and normal weight controls (18.5≤ BMI ≤24.9 kg/m2). We collected demographic, body composition, biochemical, and genotyping data by real-time PCR, and performed logistic and linear regression analyses to investigate the association of polymorphisms with severe obesity status and obesity-related quantitative parameters. Individuals with severe obesity had significantly higher anthropometric measures, blood pressure, and biochemical levels. The rs17817449 TT genotype was associated with a significantly higher risk of developing severe obesity, and distinct cytokine expression was observed across the rs17817449 genotypes. The rs6265 dominant-model and rs16147 CC genotypes were associated with triglyceride levels and childhood obesity, respectively. Finally, individuals with obesity were more likely to carry a greater number of risk alleles than those without obesity. Our study observed an important association between rs17817449 polymorphism with obesity and obesity-related traits. Additionally, rs6265 dominant-model was associated with triglyceride serum levels, and rs16147 may have a role in obesity onset.