Multi-omics study of mitochondrial dysfunction in the pathogenesis of hyperuricemia.

Abstract

Background: Mitochondrial dysfunction is linked to hyperuricemia (HUA), but its genetic pathophysiology is not yet fully understood. We employed Mendelian randomization (MR) to integrate multi-omics data and explore the associations between mitochondrial-related genes and HUA.

Methods: We conducted a summary data-based MR analysis to investigate potential targets associated with HUA by integrating mitochondrial-related DNA methylation, gene expression, and protein quantitative trait loci. Additionally, to further explore the potential associations between DNA methylation, gene expression, and protein abundance, we performed MR and co-localization analyses to examine causal relationships between candidate gene methylation and expression, as well as between gene expression and protein abundance.

Result: Through the integration of multi-omics evidence, we identified one primary gene, NUDT2, and three secondary genes, BOLA1, COMT, and HAGH. At the protein level, NUDT2 and COMT are negatively correlated with HUA risk, whereas BOLA1 and HAGH are positively correlated with HUA risk. Our analysis revealed a positive correlation between the methylation of cg06605933 in BOLA1 and its protein levels, which aligns with the negative effect of cg06605933 methylation on HUA risk. Additionally, we observed a positive correlation between NUDT2 gene expression and protein levels, confirming its beneficial effect on HUA risk. Strong co-localization support was found between the methylation of cg06605933 (PPH4 = 85.1%) in BOLA1 and protein abundance, as well as between NUDT2 gene expression (PPH4 = 96.6%) and protein levels.

Conclusion: Our study identified mitochondrial genes NUDT2, BOLA1, COMT, and HAGH as potentially associated with HUA risk, supported by evidence from various omics levels.