Study the FTO Gene rs9939609 SNP of Chronic Kidney Disease in Patients with and without T2DM

Abstract

Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally, occurring in approximately 40% of patients with type 2 diabetes mellitus (T2DM). Genetic predisposition plays a significant role in its pathogenesis. The fat mass and obesity-associated (FTO) gene variant rs9939609 has been linked to obesity, insulin resistance, and metabolic dysregulation; however, its specific contribution to DN in T2DM patients with concurrent chronic kidney disease (CKD) remains inadequately characterised, particularly in Middle Eastern populations. Objectives: To determine whether FTO rs9939609 genotype is associated with DN severity, renal function biomarkers (cystatin C, eGFR, serum creatinine), glycaemic control (HbA1c), and lipid profile in T2DM patients with CKD compared to CKD patients without diabetes and healthy controls. Methods: A case-control study comprising 225 participants stratified into three groups (n=75 each): healthy controls, CKD patients without T2DM, and CKD patients with T2DM. Genotyping of FTO rs9939609 was performed by allele- specific PCR. Biochemical parameters including HbA1c, fasting glucose, lipid profile, serum creatinine, cystatin C, and eGFR were measured using standardized laboratory protocols. Results: The AA risk allele was significantly overrepresented in CKD+T2DM patients (32.0%) vs CKD without T2DM (18.7%) and controls (16.0%; p<0.001). AA carriers showed significantly higher HbA1c (9.4±0.6%), cystatin C (2.43±0.67 mg/L), LDL-C (155.2±35.6 mg/dL), and lower eGFR (36.8±4.8 mL/min/1.73m2). Spearman partial correlation network analysis showed FTO genotype correlated independently with eGFR (ρ=−0.48), cystatin C (ρ=+0.45), and HbA1c (ρ=+0.52). Multivariate logistic regression confirmed AA genotype as an independent predictor of DN (adjusted OR 2.43; 95% CI 1.52– 5.41; p=0.003). Conclusion: FTO rs9939609 AA genotype is significantly and independently associated with increased DN risk in T2DM patients, operating through pleiotropic mechanisms involving adiposity, insulin signaling, and inflammatory pathways. FTO genotyping may serve as an adjunct biomarker for early DN risk stratification.