Metabolic syndrome (MetS) is a cluster of interrelated cardiometabolic risk factors, including abdominal obesity (increased waist circumference, WC), hypertension (elevated systolic/diastolic blood pressure, SBP/DBP), dyslipidemia (high triglycerides; low high-density lipoprotein cholesterol, HDL-C), and impaired glucose metabolism (elevated fasting blood glucose, FBG). Diagnostic criteria vary across guidelines: the NCEP ATP III defines MetS as the presence of ≥3 abnormal components, whereas the International Diabetes Federation (IDF) requires central obesity (based on ethnicity-specific WC cutoffs) plus ≥2 additional components (Third Report of the National Cholesterol Education Program NCEP, 2002; Alberti et al., 2005; Alberti et al., 2006). MetS substantially elevates the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease, and chronic kidney disease (Park et al., 2025; Lai et al., 2025; Alyousef et al., 2025; Li et al., 2023). Its global prevalence ranges from 25% to 33%, with regional variations: 25% in the United States, 30% in Bangladesh, 30.4% in Iran, 31.1% in China, 32.4% in Africa, and 33% in Brazil (Bowo-Ngandji et al., 2023; de Siqueira Valadares et al., 2022; Kalan Farmanfarma et al., 2019; Chowdhury et al., 2018; Falkner and Cossrow, 2014; Yao et al., 2021). The pathogenesis of MetS is multifactorial, involving genetic predisposition, lifestyle factors (e.g., poor diet, physical inactivity), and environmental exposures (e.g., pollutants, endocrine disruptors) (Park et al., 2024; Jeong and Choi, 2024). Recent advances in genomics have identified multiple susceptibility genes and polymorphic variants contributing to MetS susceptibility, highlighting its complex genetic architecture.

The fat mass and obesity-associated gene (FTO), which encodes an RNA N6-methyladenosine demethylase, has been implicated in regulating multiple components of MetS. Human studies have demonstrated tissue-specific associations between FTO expression and metabolic parameters. Samaras et al. (2010) reported that subcutaneous adipose tissue FTO mRNA expression correlated positively with WC and FBG in patients undergoing abdominal surgery. Similarly, Grunnet et al. (2009) found that subcutaneous adipose FTO expression in Danish twins showed an inverse relationship with HDL-C levels, suggesting a role in lipid metabolism. Mouse models further reveal the diverse metabolic functions of FTO across tissues. Wang et al. (2015) demonstrated that adipose-specific FTO knockout mice exhibited enhanced triglyceride clearance and reduced serum triglyceride concentrations through mechanisms involving ANGPTL4 upregulation. In contrast, Luse et al. (2022) showed that smooth muscle cell-specific FTO deletion led to significantly reduced SBP and DBP without affecting body weight, revealing a novel role in vascular function regulation. These findings collectively highlight the pleiotropic effects of FTO across different tissues in modulating MetS components.

The human FTO gene is located on chromosome 16q12.2 and consists of 9 exons interspersed with 8 introns. Two obesity-associated single-nucleotide polymorphisms (SNPs), rs9939609 and rs17817449, reside within intron 1 of FTO. The rs9939609 variant, a thymine-to-adenine transversion (g.53786615T>A), has been functionally linked to allele-specific expression differences. Villalobos-Comparán et al. (2008) quantified FTO mRNA in subcutaneous adipose tissue from 31 Mexican women, revealing 1.65-fold higher expression in A allele carriers of rs9939609 compared to TT homozygotes. Berulava et al. (2010) extended these findings through transcript quantification in peripheral blood mononuclear cells and skin biopsies, showing A allele carriers exhibited 1.38-fold and 1.31-fold higher FTO mRNA levels than TT genotypes, respectively. These expression differences were further corroborated in leukocyte samples by Karra et al. (2013), who observed 1.22-fold increased FTO transcription in AA homozygotes compared to T-allele carriers. The rs17817449 variant (g.53779455T>G), positioned approximately 7.2 kb upstream of rs9939609 within the same intronic region, may influence FTO expression through cis-regulatory mechanisms. This variant was associated with elevated risks of T2DM and dyslipidemia in a Chinese Han population (Zhang et al., 2023), suggesting its potential role in modulating metabolic phenotypes via FTO dysregulation.

This retrospective case-control study aims to evaluate whether FTO rs9939609 and rs17817449 polymorphisms are associated with MetS susceptibility, and to elucidate the pathways through which these polymorphisms influence MetS susceptibility.

This study provides robust evidence that the FTO polymorphisms rs9939609 and rs17817449 significantly increase MetS risk in a Chinese population, primarily through detrimental effects on glucose and lipid metabolism. Key findings include: 1) The A allele of rs9939609 and G allele of rs17817449 were significantly enriched in MetS patients; 2) Both variants demonstrated allele dose-dependent worsening of MetS components; and 3) Dyslipidemia and hyperglycemia work as the primary pathways linking FTO variants to MetS susceptibility. While large-scale GWAS have primarily established FTO’s link to obesity (Frayling et al., 2007), our results refine and extend this paradigm by demonstrating that its metabolic impact is substantially mediated through glucolipid pathways. Our findings not only align with prior evidence linking FTO to general metabolic dysregulation (Samaras et al., 2010; Grunnet et al., 2009; Wang et al., 2015; Luse et al., 2022), but, more importantly, quantify the substantial mediating role (45%–86%) of these metabolites—a relationship suggested but not rigorously established in previous, smaller-scale studies.

Our findings extend prior research on FTO and metabolic traits while also revealing important distinctions. While earlier large-scale GWAS and meta-analyses have primarily and robustly linked FTO variants to elevated BMI and obesity risk (Frayling et al., 2007; Quan et al., 2015), our mediation analysis demonstrates that a substantial portion of MetS risk is attributable to dyslipidemia and hyperglycemia, partially independent of absolute adiposity measures. Given that these glucolipid abnormalities are not fully explained by adiposity, our data suggest that FTO’s metabolic effects may operate through parallel pathways: one influencing energy balance (appetite/adiposity) and another more directly perturbing hepatic lipid metabolism and insulin signaling. Notably, the rs17817449 G allele showed stronger associations with elevated SBP in controls, an observation that, while not aligning with the primary metabolic profile of FTO, parallels its broader association with cardiovascular risk factors. Although such direct associations with blood pressure are uncommon for FTO variants, isolated reports exist, underscoring the need for further investigation (Sharma and Badaruddoza, 2024). Finally, discrepancies with studies predominantly conducted in European populations (Górczyńska-Kosiorz et al., 2024; Ślęzak et al., 2018) may reflect ethnic-specific genetic architectures or gene-environment interactions, as suggested by trans-ethnic meta-analyses which have noted heterogeneity in FTO effect sizes across ancestries (Wang et al., 2012). Furthermore, the LD analysis revealed a moderate linkage between rs9939609 and rs17817449 in the overall population (r² = 0.24), which was notably stronger in the MetS group (r² = 0.37) than in controls (r² = 0.11). This differential LD pattern may reflect distinct haplotype structures contributing to MetS susceptibility, or could be a consequence of the disease-associated allele distribution.

Our mediation analysis identified triglycerides, HDL-C, and FBG as the significant mediators linking FTO polymorphisms to MetS, while BP did not emerge as a primary pathway. This finding aligns with the predominant metabolic function of FTO. The gene’s role as an RNA m6A demethylase places it squarely within pathways governing hepatic lipogenesis (Hu et al., 2020; Chen et al., 2018; Tang et al., 2023), adipocyte differentiation (Chen et al., 2022), and insulin signaling (Chen et al., 2022; Zhuang et al., 2019), thereby directly impacting circulating lipid and glucose levels. Conversely, hypertension pathogenesis is largely driven by separate mechanisms, such as renal sodium handling, vascular resistance, and the renin-angiotensin system (Ma et al., 2023), in which FTO does not play a well-established central role. This mechanistic divergence is corroborated by our genotype-phenotype analysis (Tables 4 and 5), where both rs9939609 and rs17817449 exhibited clear, dose-dependent effects on triglyceride and FBG levels, but not on SBP or DBP. Therefore, the contribution of these specific FTO variants to MetS appears to be channeled predominantly through the dysregulation of glucolipid metabolism, rather than through direct effects on blood pressure.

The mechanisms by which FTO rs9939609 and rs17817449 polymorphisms contribute to MetS likely involve epigenetic regulation of metabolic genes and disruption of energy homeostasis, mirroring findings from related obesity-associated FTO variants. First, these intronic variants may exert their metabolic effects by modulating FTO expression, thereby altering RNA methylation (m6A) patterns of downstream targets critical for lipid and glucose metabolism. Previous studies have consistently shown that the A allele carriers of rs9939609 exhibit elevated FTO mRNA levels in subcutaneous adipose tissue (Villalobos-Comparán et al., 2008; Villalobos-Comparán et al., 2017), skin biopsies (Karra et al., 2013), and peripheral blood cells (Berulava et al., 2010). This upregulation disrupts the expression of key metabolic regulators including sterol regulatory element binding protein-1c (Hu et al., 2020; Chen et al., 2018; Tang et al., 2023), peroxisome proliferator-activate receptor-alpha (Wei et al., 2022), peroxisome proliferator-activated receptor-gamma (Chen et al., 2022), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Zhuang et al., 2019), and carbohydrate responsive element binding protein (Tang et al., 2023). These transcription factors collectively govern critical metabolic processes such as lipogenesis, adipogenesis, and insulin sensitivity. Notably, the pivotal role of FTO in lipid metabolism is supported by large-scale genetic studies that link its risk variants to altered blood lipid profiles, particularly elevated triglycerides, independently of BMI (Fall et al., 2013; Jalili et al., 2021). Second, FTO variants may influence appetite regulation and energy intake through ghrelin signaling (Karra et al., 2013). The A allele of rs9939609 has been linked to decreased m6A methylation of ghrelin mRNA, leading to elevated circulating ghrelin levels. This epigenetic dysregulation promotes increased hunger and caloric intake, providing a mechanistic explanation for the allele dose-dependent deterioration in triglycerides, HDL-C, and FBG observed in our study. Together, these mechanisms suggest that FTO-associated MetS risk arises from a combination of direct effects on glucolipid metabolism and indirect effects on feeding behavior. This molecular model directly explains our clinical findings, providing a plausible foundation for the prominent mediating effects of triglycerides, HDL-C, and FBG, and thereby bridging the gap between the FTO genotype and systemic metabolic dysfunction.

The strong associations between FTO polymorphisms and MetS risk, particularly through dyslipidemia and hyperglycemia, have important clinical and public health implications. Our findings suggest that genetic screening for FTO variants could help identify high-risk individuals before overt metabolic dysfunction develops. Given the allelic dose-dependent worsening of triglycerides, HDL-C, and FBG, carriers of risk genotypes may benefit from early lifestyle interventions or pharmacological strategies targeting lipid and glucose metabolism. Additionally, the high mediation proportions of triglycerides and HDL-C suggest that lipid-lowering therapies might be particularly effective in attenuating genetic risk in this population. These results align with emerging precision medicine approaches for MetS, where genetic profiling could guide risk stratification and tailored prevention strategies.

Several limitations of this study should be acknowledged. First, the cross-sectional design precludes causal inferences regarding the temporal relationship between FTO polymorphisms and MetS development. Second, while we adjusted for major confounders, residual confounding from unmeasured factors (e.g., dietary patterns, physical activity intensity, or environmental exposures) may persist. Third, this was a candidate-gene study focusing on two specific FTO polymorphisms (rs9939609 and rs17817449) based on our previous research findings (Zhang et al., 2023; Song et al., 2023; Song et al., 2025). A genome-wide association study might reveal additional genetic variants associated with MetS in this population. These limitations highlight the need for longitudinal, multi-ethnic studies incorporating comprehensive omics approaches to validate and extend our findings.

In conclusion, the polymorphisms in the first intron of FTO are associated with high risk of MetS, which is strongly modulated by triglycerides, HDL-C and FBG. These findings highlight the necessity for population-specific approaches in genetic risk assessment for MetS.