Exploration of the effects of 66 mitochondria-associated proteins on different cardiomyopathies: A bidirectional 2-sample mendelian randomization study

The aim of this study was to apply bidirectional Mendelian randomization (MR) to assess and investigate the causal associations between mitochondrial DNA copy number (mtDNA-CN), mitochondrial-associated proteins and cardiomyopathy. The mtDNA-CN and MAP from the IEU Open GWAS database were screened for strong associations with 4 different cardiomyopathy-associated single nucleotide polymorphisms (SNPs) in the IEU Open GWAS and Finnish databases, respectively, and causal associations were investigated using the inverse variance weighting method, the MR-Egger regression method, the weighted median method, the weighted mode method, and the simple mode method. method to explore causality; meanwhile, we used the Cochran Q test to assess the variability of SNPs. Horizontal pleiotropy of SNPs was examined by MR-Egger regression analysis and MR-PRESSO method. Sensitivity analyses were performed using the "Leave-One-Out (LOO)" method to determine whether the MR results would be interfered by a single SNP. MR analyses of mtDNA-CN, mitochondria-associated proteins, and different cardiomyopathies, respectively, with IVW as the primary analytical method, showed a statistically significant association between mtDNA-CN and pharmacological cardiomyopathy, P < .05. Statistical significance was found between 2 mitochondria-associated proteins (dihydrolipoyl dehydrogenase, mitochondrial apoptosis-inducing factor 1) and hypertrophic cardiomyopathy, both with P < .05. Six mitochondria-associated proteins (mitochondrial 39S ribosomal protein L33, ribosomal recycling factor, mitochondrial leucine-rich pentatricopeptide repeat motif-containing protein, serine protease high-temperature requirement protease A2, mitochondrial peptide methionine sulfoxide reductase, and mitochondrial input endomembrane transporter enzyme subunit translocase of inner mitochondrial membrane 14) and dilated cardiomyopathy were statistically significant, both with P < .05. Screening for 2 mitochondria-associated proteins (nicotinamide adenine dinucleotide dehydrogenase [ubiquinone] flavoprotein 2, and mitochondrial input endomembrane transporter enzyme subunit translocase of inner mitochondrial membrane 14, prot-a-847) and alcoholic cardiomyopathy was statistically significant，P < .05. Statistical significance was found between 1 mitochondria-associated protein (mitochondrial peptide chain release factor 1) screened and pharmacological cardiomyopathy, P < .05. Sensitivity analyses of all MR results: the Cochran Q test, MR-Egger intercept test, MR-Presso global test, and LOO sensitivity test No significant heterogeneity or horizontal pleiotropy was found at any time (all P > .05). There were causal associations between mtDNA-CN, mitochondria-associated proteins and cardiomyopathy, and mtDNA-CN and mitochondria-associated proteins had a certain predictive value for the condition and prognosis of patients with cardiomyopathy.