Mitochondrial-related pathogenic genes in varicose veins: A multi-omics Mendelian randomization study

Objectives The dysfunction of mitochondria has been associated with the development of varicose veins (VV), but the specific mitochondrial-related genes and their roles in VV have not been fully elucidated. We employed Mendelian randomization (MR) and colocalization analysis to investigate the association between mitochondrial-related genes and VV by integrating multi-omics data. Methods We utilized genome-wide association study (GWAS) summary data obtained from UKB and the FinnGen databases. Data on DNA methylation quantitative trait loci(mQTL), gene expression quantitative trait loci (eQTL), and protein expression quantitative trait loci(pQTL) derived from blood samples were considered as exposures. We identified mitochondria-related genes from the MitoCarta3.0 database and integrated these with mQTL, eQTL, and pQTL data using the SMR approach. Subsequently, colocalization analysis was conducted to evaluate shared causal genetic variants. Results SMR and colocalization analyses identified 122 methylation sites, 36 differentially expressed genes, and 4 proteins associated with VV. Validation in the FinnGen cohort confirmed 25 methylation sites and 18 genes. By integrating mQTL and eQTL data, higher genetically predicted expression levels of HADHA and BCL2L1 were causally associated with a reduced risk of VV. Notably, PARK7 emerged as a key protective gene in the intersection of mQTL, eQTL, and pQTL analyses, where both higher gene expression and higher protein abundance were protectively associated with VV risk. Conclusions Our findings reveal critical mitochondrial-related genes that exert a protective effect against VV, providing novel insights into disease pathogenesis and identifying potential molecular targets for prevention and therapy.