Mitochondria-related pathogenic genes in acute and chronic kidney disease: a Mendelian randomization study.

This study aims to utilize summary-data-based Mendelian randomization (SMR) to explore the potential associations linking mitochondrial-related genes with acute kidney injury (AKI) and chronic kidney disease CKD. This study utilized mitochondrial-related genes from the MitoCarta3.0 database, alongside DNA methylation (mQTLs), gene expression (eQTLs), and protein expression (pQTLs) quantitative trait loci data. We obtained summary statistics from genome-wide association studies for AKI and CKD from the United States Million Veteran Program, with subsequent validation in the UK Biobank. The SMR method, complemented by colocalization analysis, was used to assess associations. We further performed validation using kidney cortex-specific eQTL data from Genotype-Tissue Expression project and single-cell transcriptome data from the KPMP database. In the discovery datasets, SMR analysis identified 174 mQTLs, 64 eQTLs, and 20 pQTL associated with AKI risk, and 253 mQTLs, 80 eQTLs, and 23 pQTLs associated with CKD risk. A total of 32 mQTLs, 16 eQTLs and 9 pQTLs were identified as common signals associated with both AKI and CKD risks. Specifically, FASN, DELE1, SARS2, NDUFB2, and ATP23 were significantly associated with both AKI and CKD risks, while ATAD3B and GCDH were CKD-specific signals. Notably, the shared gene ATP23 was identified as a risk factor for both AKI and CKD in kidney cortex tissue. Furthermore, ATAD3B was validated as a potentially protective factor for CKD, although the effect size was modest (OR 0.95, 95% CI 0.90-1.00). This study utilized the SMR method to identify potential risk and protective genes for AKI and CKD, revealing a molecular link between mitochondrial-related genes and renal failure.