Genetic and expression evidence supports FTO rs9939609 as a key susceptibility marker for type 2 diabetes and obesity in Thai adults

Variants in the fat mass and obesity-associated ( FTO ) gene are widely linked to obesity and type 2 diabetes mellitus (T2DM), yet their functional relevance in Asian populations remains unclear. This study examined the association of two common FTO intron-1 variants, rs9939609 and rs1421085, with T2DM, obesity, and cardiometabolic traits in a Thai cohort ( n = 798; 350 controls and 448 cases), and evaluated their relationship with FTO messenger RNA (mRNA) expression. Both variants showed significant additive associations with T2DM and obesity, with rs9939609 demonstrating the strongest effect (per-allele OR = 1.60, 95% CI: 1.17–2.19; P = 0.003). Associations with T2DM remained robust after stratification by obesity status. The two SNPs were in strong linkage disequilibrium, and conditional analyses indicated that rs9939609 represented the primary association signal. In a subset of 152 participants, rs9939609 risk-allele carriers exhibited significantly higher FTO mRNA expression in peripheral blood leukocytes, whereas rs1421085 showed no expression differences. These findings, based on population-specific criteria and genetic modeling, demonstrate the additive contribution of FTO variants to metabolic risk in Thai adults and highlight rs9939609 as the major genetic signal at this locus, potentially acting through increased FTO expression. However, the cross-sectional design precludes causal inference.