High Prevalence of the FTO T allele (rs9939609 T>A) and its association with a high risk of Type 2 diabetes or metabolic-associated steatotic liver disease (MASLD) in the Mexican population

Introduction and Objectives

The FTO rs9939609 (T>A) polymorphism has been associated with obesity and metabolic disorders, including type 2 diabetes and MASLD. This study examined the distribution of the FTO (T>A) polymorphism in Native and admixed populations and its impact on an admixed Mexican cohort's anthropometric and metabolic profiles.

Materials and Patients

In this cross-sectional study, we evaluated 684 unrelated adults from various regions of West Mexico, categorizing them into Native, Mestizo (admixed), and Mestizo-Caucasian groups based on ancestry. Genotyping for the FTO rs9939609 polymorphism was performed using an allele discrimination assay via Real-Time PCR. Given the low prevalence of the A allele among the Mestizo subjects (n=333), the biochemical and anthropometric measurements were adjusted by genotypes AA+AT vs. TT. Anthropometric measurements were assessed using body circumferences and electrical bioimpedance. Metabolic profiles were evaluated by measuring glucose, insulin, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Metabolic abnormalities were defined as follows: hypercholesterolemia (HCL) with TC ≥200 mg/dL, high LDL-c (H-LDL) with LDL-c ≥130 mg/dL, hypoalphalipoproteinemia (HALP) with HDL-c <40 mg/dL, hypertriglyceridemia (HTG) with TG ≥150 mg/dL, hyperglycemia (HGL) with fasting glucose ≥100 mg/dL, hyperinsulinemia (HINS) with insulin >9 µUI/dL, and insulin resistance (IR) with HOMA-IR ≥2.5. Principal Component Analysis (PCA) was used to visualize genetic divergence focusing on the TT genotype. Univariate and multivariate logistic regression analyses were conducted to assess the risk association between the TT genotype and metabolic abnormalities. Statistical analyses were performed using R Studio and SPSS software.

Results

The Huicholes Native population exhibited the highest T allele frequency and TT genotype frequency (94% and 89%), followed by Mestizos from Guadalajara (74% and 56%). In contrast, Mestizo-Caucasians from Cuquio had the lowest T allele frequency (28.1%) and the highest A allele frequency (32.4%) within the Mestizo-Caucasian population of Villa Purificación. Genetic distance analysis using PCA based on FTO TT genotype prevalence revealed that the Mestizo-Caucasian population formed a distinct cluster, while Native populations displayed the highest genetic divergence among groups. When analyzing the Mestizos by genotype (AA+AT vs. TT), no significant differences were found in BMI or body fat percentage. However, metabolic profiles of TT genotype carriers showed higher waist-to-height ratios (0.49±0.08 vs. 0.52±0.07, p<0.001), insulin levels (8.8±5.2 vs. 10.8±7.3 µUI/dL, p<0.041), TG (125.8±65.3 vs. 141.8±66.5 mg/dL, p<0.017), and VLDL-c (25.6±14.2 vs. 29.1±14.8 mg/dL, p<0.015). Univariate analysis indicated that the TT genotype was associated with a higher risk of HTG (OR=1.7, 95%CI:1.07-2.73, p<0.027), IR (OR=1.79, 95%CI:1.06-3.07, p<0.031), and HGL (OR=2.77, 95%CI:1.5-5.36, p<0.002) compared to AA+AT genotypes. Multivariate logistic regression further confirmed that TT genotype carriers had a higher risk of HGL compared to AA+AT genotype carriers (OR=2.50, 95%CI:1.213-5.152, p<0.013).

Conclusions

The T allele of the FTO (rs9939609 T>A) is more prevalent in Native and Mestizo populations and is associated with higher risks of IR, HTG, and HGL, all of which are linked to type 2 diabetes and MASLD. These results highlight a genetic predisposition to metabolic diseases in populations with significant Amerindian ancestry, particularly in hepatopathogenic environments.

Ethical statement: The Institutional Review Board approved this study, and participants signed a written informed consent form prior to entry.

Declaration of interests: None.

Funding: Supported by the University of Guadalajara, Guadalajara, Mexico – Programa de Fortalecimiento de Institutos, Centros y Laboratorios.