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

Area of Science:

• Genetics
• Mitochondrial Biology
• Systems Biology

Background:

• Mitochondrial dysfunction is implicated in hyperuricemia (HUA).
• The genetic underpinnings of HUA, particularly concerning mitochondrial genes, remain incompletely understood.
• Integrating multi-omics data offers a powerful approach to elucidate these complex relationships.

Purpose of the Study:

• To investigate the genetic associations between mitochondrial-related genes and hyperuricemia (HUA) using Mendelian randomization (MR).
• To explore the causal relationships between DNA methylation, gene expression, and protein abundance for candidate mitochondrial genes.
• To identify specific mitochondrial genes and their molecular mechanisms contributing to HUA risk.

Main Methods:

• Summary data-based Mendelian randomization (MR) analysis integrating multi-omics data (DNA methylation, gene expression, protein quantitative trait loci).
• MR and co-localization analyses to examine causal links between gene methylation, expression, and protein abundance.
• Multi-omics data integration to identify and validate associations between mitochondrial genes and HUA.

Main Results:

• Four mitochondrial genes (NUDT2, BOLA1, COMT, HAGH) were identified as potentially associated with HUA risk.
• NUDT2 and COMT showed a negative correlation with HUA risk at the protein level, while BOLA1 and HAGH showed a positive correlation.
• Co-localization analyses supported causal links between BOLA1 methylation and protein abundance, and between NUDT2 gene expression and protein levels.

Conclusions:

• Mitochondrial genes NUDT2, BOLA1, COMT, and HAGH are potentially associated with hyperuricemia (HUA) risk.
• These associations are supported by integrated evidence across multiple omics levels, including gene expression and protein abundance.
• The findings provide novel insights into the genetic pathophysiology of HUA involving mitochondrial pathways.