The fat-mass and obesity-associated (FTO) gene rs9939609 T allele is prominent among the native Mexican population and is associated with risk for type 2 diabetes and metabolic dysfunction-associated steatotic liver disease

Maricruz Sepulveda-Villegas¹Arturo Panduro¹Leonardo Leal Mercado¹Juan Pablo Cardenas-Benitez¹Claudia Ojeda-Granados²Sonia Roman^1*

• ¹University of Guadalajara, Guadalajara, Mexico
• ²Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania,, Catania, Italy

Background: The fat mass and obesity-associated (FTO) rs9939609 T>A polymorphism is associated with excess body fat and metabolic disturbances, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the genetic effect of the T and A alleles on the development of these diseases may vary among populations. Objective: This study aimed to determine the distribution of the FTO rs9939609 T>A polymorphism in West Mexican populations with variable genetic ancestry and analyze its effect on an admixed cohort's anthropometric and metabolic profile. Methods: In a cross-sectional study, 684 unrelated adults from West Mexico were included. Subjects were grouped as Amerindian (Wixarika and Nahuas) or admixed: Mestizo-Caucasians (Cuquio, San Miguel-Los Altos, and Villa Purificación) and Mestizo-Guadalajara (Mestizo-GDL). FTO genotyping was determined by an allelic discrimination assay. Assessment of anthropometrics, diet composition, and metabolic profile among 333 Mestizo-GDL subjects and their association with metabolic risk factors was conducted considering the dominant model (AA+AT vs. TT). Results: The Wixarika group exhibited the highest T allele (94%) and TT genotype frequencies (89%), followed by Mestizo-GDL (74% and 56%, respectively) among the Amerindians. Among the Mestizo-Caucasians, Cuquio had the lowest T allele frequency (28.1%), while the highest A allele frequency (32.4%) was found in Villa Purificación. No significant effect of FTO genotype on BMI/body fat was observed. However, the TT carriers exhibited higher waist-to-height ratios (0.52 ± 0.07 vs. 0.49 ± 0.08), insulin levels (10.8 ± 7.3 vs. 8.8 ± 5.2 µUI/dL), triglycerides (141.8 ± 66.5 vs. 125.8 ±65.3 mg/dL), and VLDL-c (29.1 ± 14.8 vs. 25.6 ± 14.2 mg/dL) than AA+AT carriers. The TT genotype was associated with higher odds of hypertriglyceridemia (HTG) (OR=1.7,95%CI=1.07-2.73,p=0.027), insulin resistance (IR) (OR=1.79,95%CI=1.06-3.07, p=0.031), and hyperglycemia (HGL) (OR=2.77, 95%CI=1.5-5.36, p=0.002). Multivariable logistic regression confirmed that TT genotype carriers had greater odds of HGL (OR=2.50,95%CI=1.2-5.15, p=0.013). Conclusion: The FTO T allele was prominent among native Mexicans. In contrast, the A allele prevailed among the Mestizo with higher European ancestry. TT genotype carriers had higher odds of IR, HTG, and HGL, highlighting the genetic predisposition to T2D and MASLD in populations exposed to obesogenic and hepatopathogenic environments.