Exploring the relationship between uric acid-to-HDL cholesterol ratio and vascular calcification: evidence from clinical, genetic, and network-based analyses.

BACKGROUND: Vascular calcification (VC) is a multifactorial process associated with adverse cardiovascular outcomes. The uric acid to high-density lipoprotein cholesterol ratio (UHR) has been proposed as a composite metabolic biomarker that reflects the balance between pro-oxidative and anti-inflammatory processes. However, its association with VC and the underlying mechanisms remain incompletely understood. METHODS: This study integrated clinical association analysis, Mendelian randomization (MR), and network-based approaches. A retrospective cross-sectional analysis was conducted in 627 clinically stable cardiology inpatients, with aortic arch calcification (AoAC) assessed using chest radiographs. Multivariable logistic regression and restricted cubic spline analyses were used to examine the association between UHR and AoAC. Two-sample MR was performed to assess the potential causal effects of uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) on abdominal aortic calcification (AAC), a macrovascular calcification phenotype. Network-based analysis was conducted to explore potential molecular mechanisms. RESULTS: Higher UHR levels were significantly associated with greater AoAC severity, which remained after adjusting for standard cardiovascular risk factors. MR analysis showed no significant genetic association between genetically predicted UA and AAC, whereas genetically predicted HDL-C showed an inverse association with AAC in the primary IVW analysis, but this was not consistently supported across sensitivity methods. Network-based analyses identified enrichment in inflammation- and remodeling-related pathways, including MAPK and PI3K-Akt signaling, with key hub targets such as TNF, AKT1, and EGFR. CONCLUSION: Higher UHR levels were associated with greater VC burden in clinically stable cardiology inpatients. The clinical, genetic, and network-based findings provide complementary evidence suggesting that UHR may reflect the combined influence of multiple metabolic and inflammatory processes associated with VC, rather than the direct effect of any single component.