Predictive performance of HOMA-IR and TyG index across FTO rs9939609 genotypes in type 2 diabetes mellitus

Background:The fat mass and obesity-associated (FTO) gene variant rs9939609 has been linked to obesity, Insulin Resistance (IR), and Type 2 Diabetes Mellitus (T2DM).Conventional IR indicators such as Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) require insulin measurement, whereas the triglyceride-glucose (TyG) index offers a cost-effective alternative that reflects metabolic disturbances involving glucose and lipid metabolism.This study assessed whether the predictive performance of IR indices differs across FTO rs9939609 genotypes in North India. Methods:A case-control study was conducted among 120 T2DM patients and 120 age-and sex-matched healthy controls.Fasting glucose, triglycerides, lipid profile, and insulin levels were measured.HOMA-IR and TyG indices were calculated.FTO rs9939609 (T>A) genotyping was performed using Polymerase Chain Reaction -Restriction Fragment Length Polymorphism (PCR-RFLP) followed by ScaI digestion.Associations between IR indices and genotype models were examined using logistic regression under additive, recessive, and dominant models.Receiver operating characteristic (ROC) analysis evaluated the discriminatory performance of the indices for T2DM. Results:The A allele was significantly more frequent in T2DM cases than controls (43.9% vs. 27.9%,p<0.001.Both TyG and HOMA-IR values increased progressively from TT < AT < AA genotypes.In the additive model, TyG (OR=2.84;95% CI: 1.80-4.47)and HOMA-IR (OR=2.39;95% CI: 1.53-3.73)were associated with T2DM.ROC analysis demonstrated superior discriminatory performance of TyG, particularly under the dominant model (AUC=0.742vs. 0.666 for HOMA-IR). Conclusions:FTO rs9939609 strongly influences IR and T2DM susceptibility.The TyG index outperforms J o u r n a l P r e -p r o o f HOMA-IR across genotype models, making it a practical and genetically informed screening marker.