Interplay of urea nitrogen, uric acid, and HDL in mediating cystatin C's role in metabolic syndrome: evidence from NHANES 1999-2004

Abstract

Background Metabolic syndrome (MetS) significantly increases the risk for cardiovascular diseases and diabetes. This study investigates the associations and interactions between cystatin C, urea nitrogen, uric acid, and high-density lipoprotein (HDL), assessing their collective impact on MetS using data from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Methods We conducted a retrospective longitudinal analysis on 54,555 participants from NHANES. Multivariate logistic regression models were employed to evaluate the impact of cystatin C on MetS, adjusting for demographic and lifestyle factors. Mediation analysis quantified the effects mediated by urea nitrogen, uric acid, and HDL. Generalized additive models (GAM) explored non-linear relationships and interactions among biomarkers. Stratified analysis further dissected these relationships across demographic groups, such as sex, age and BMI, to assess variability in biomarker impacts. Results Regression analysis demonstrated a robust association between increased cystatin C levels and higher MetS risk (adjusted OR for highest quartile: 1.69, 95% CI: 1.31–2.18, P < 0.001). Mediation analysis indicated that urea nitrogen and uric acid mediated 24.19% and 48.13% of the effect of cystatin C on MetS risk. HDL moderated these effects, reducing the likelihood of MetS where higher levels of HDL were present (mediated 52.58%). The three-way interaction between MetS, HDL, and urea nitrogen was also significant (estimate − 0.00232, P < 0.003). GAM shows a non-linear relationship between urea nitrogen and cystatin C, where cystatin C levels increase with urea nitrogen up to approximately 60 mg/dL, after which they decrease until about 60 mg/dL and increase until about 80 mg/dL. Stratified analysis underscored that the impact of these biomarkers varies significantly by age, with stronger associations observed in older adults (≥ 65 years), and socioeconomic status, where lower economic groups (PIR > 3.5) showed heightened vulnerability. Conclusions The study confirms the crucial role of cystatin C as a predictor of MetS, influenced by its interactions with urea nitrogen, uric acid, and HDL. The differential impact across demographic profiles emphasizes the need for personalized approaches in the management and prevention of MetS. These insights pave the way for targeted therapeutic strategies that consider individual and demographic-specific metabolic profiles.