Multi-Trait Genetic Association Reveal a Central Mechanism in the Comorbidity of Hyperuricemia and Hyperlipidemia

Abstract

Background: Hyperuricemia and hyperlipidemia frequently coexist in metabolic syndrome, yet their shared pathogenic mechanisms remain insufficiently elucidated. Identifying convergent molecular pathways may provide novel therapeutic targets for metabolic comorbidity. Methods: A multi-omics strategy integrating multi-trait genome-wide association analysis (MTAG), weighted gene co-expression network analysis (WGCNA), protein–protein interaction (PPI) network construction, and functional enrichment analysis was employed to identify common genetic drivers of hyperuricemia and hyperlipidemia. To validate the bioinformatic findings, a high-purine and high-fat diet-induced quail model of combined hyperuricemia and hyperlipidemia was established, and the expression levels of NAMPT and SIRT1 were assessed in serum and metabolic tissues. Results: Multi-trait genetic association analysis revealed that the NAMPT–SIRT1 signaling pathway demonstrated a 66.7% genetic overlap and a 100% target gene detection rate, accompanied by significant enrichment in the nicotinamide metabolic pathway (P=2.1×10-12). In vivo validation showed markedly decreased expression of NAMPT and SIRT1 in both serum and liver tissues of comorbid model animals, aligning with the predicted molecular dysregulation pattern. Conclusion: By integrating multi-omics screening with experimental validation in an avian model, this study highlights the NAMPT–SIRT1 axis as a core molecular hub linking hyperuricemia and hyperlipidemia. These findings provide mechanistic insight into metabolic comorbidity and suggest NAMPT–SIRT1 signaling as a promising target for therapeutic intervention and drug development.