Salum, Kaio C. R.da Silva Assis, Izadora Sthephaniede Almeida Kopke, ÚrsulaPalhinha, Lohannade Medeiros Abreu, GabriellaGouvêa, Laura W.Teixeira, Myrela R.Mattos, Fernanda C. C.Nogueira Neto, José F.de Freitas Martins Felício, RafaelaRosado, Eliane L.Zembrzuski, Verônica M.Campos Junior, MarioMaya-Monteiro, Clarissa M.Cabello, Pedro H.Carneiro, João R. I.Bozza, Patrícia T.Kohlrausch, Fabiana B.da Fonseca, Ana C. P.2025-02-132025-02-132025-01-31Salum, K. C. R., da Silva Assis, I. S., de Almeida Kopke, Ú., Palhinha, L., de Medeiros Abreu, G., Gouvêa, L. W., Teixeira, M. R., Mattos, F. C. C., Nogueira Neto, J. F., de Freitas Martins Felício, R., Rosado, E. L., Zembrzuski, V. M., Campos Junior, M., Maya-Monteiro, C. M., Cabello, P. H., Carneiro, J. R. I., Bozza, P. T., Kohlrausch, F. B., & da Fonseca, A. C. P. (2025). FTO rs17817449 variant increases the risk of severe obesity in a Brazilian cohort: A case-control study. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 18, 283-303. https://doi.org/10.2147/DMSO.S4514011178-700710.2147/DMSO.S451401http://hdl.handle.net/10034/629249© 2025 The Author(s). This work is published and licensed by Dove Medical Press Limited.PURPOSE: 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 LEPR rs1137101, POMC rs1042571, LEP rs7799039, BDNF rs6265, FTO rs17817449, CART rs121909065, and NPY rs16147/rs5574. PATIENTS AND METHODS: 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. RESULTS: Individuals with severe obesity had significantly higher anthropometric measures, blood pressure, and biochemical levels. The FTO rs17817449 TT genotype was associated with a significantly higher risk of developing severe obesity, and distinct cytokine expression was observed across the FTO rs17817449 genotypes. The BDNF rs6265 dominant-model and NPY 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. CONCLUSION: Our study observed an important association between FTO rs17817449 polymorphism with obesity and obesity-related traits. Additionally, BDNF rs6265 dominant-model was associated with triglyceride serum levels, and NPY rs16147 may have a role in obesity onset.Licence for this article: cc by-nchttps://creativecommons.org/licenses/by-nc/4.0/FTOPolymorphismsLeptin-melanocortin pathwayCytokines expressionObesityArticleDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy2025-02-13