Abstract
BACKGROUND AND AIMS: The polymorphisms in fat mass and obesity-associated gene (FTO) have been implicated in metabolic dysregulation. This study aimed to investigate the associations between the FTO rs9939609 and rs17817449 polymorphisms and MetS risk, and to assess whether glucolipid parameters mediate these associations. METHODS: A hospital-based cross-sectional study involving 701 adults was conducted. MetS was diagnosed according to the criteria of the International Diabetes Federation (2005). Clinical data were collected for all participants. Genotyping of rs9939609 and rs17817449 was performed via polymerase chain reaction-restriction fragment length polymorphism. Logistic regression and mediation analysis were used to evaluate genetic associations and mediating effects. RESULTS: The MetS group showed higher frequencies of rs9939609 A allele (14.01% vs. 6.09%, P < 0.001) and rs17817449 G allele (16.94% vs. 12.18%, P = 0.012) compared to controls. Rs9939609 AA genotype carriers had the highest MetS risk (OR = 3.58, 95% CI: 1.08-11.88) and exhibited allelic dose-dependent worsening of triglycerides, high-density lipoprotein cholesterol (HDL-C), and fasting blood glucose (FBG) (all P < 0.05). Similarly, rs17817449 G allele was linked to elevated triglycerides, reduced HDL-C, higher FBG, and increased systolic blood pressure (all P < 0.05). Mediation analysis revealed triglycerides, HDL-C, and FBG as significant mediators for the associations of rs9939609 and rs17817449 with MetS (all P < 0.001). CONCLUSION: FTO rs9939609 and rs17817449 polymorphisms are strongly associated with MetS risk, primarily by increasing triglyceride and glucose levels and decreasing HDL-C. These findings highlight the pivotal role of FTO variants in metabolic dysregulation and suggest potential targets for early intervention of MetS.