Bidirectional Two-Sample Mendelian Randomization Analysis Unveils a Causal Correlation of Mitochondrial Function-Related Proteins with the Risk of Diabetic Nephropathy

Abstract

Objective. The genuine causal nexus between mitochondrial function-related proteins and diabetic nephropathy remains enigmatic and arduous to delineate conclusively. In this study, we employed a bidirectional two-sample Mendelian randomization analysis, a robust approach, to scrutinize and discern the causal interplay between them. Methods. In this investigation, the datasets pertaining to diabetic nephropathy and mitochondrial function-related proteins were meticulously extracted from the comprehensive IEU OpenGWAS Project database. The principal analytical method employed was the inverse variance weighted approach. In addition, MR-Egger regression, simple median, and weighted median methodologies were utilized as supplementary tools to interrogate the causal associations of mitochondrial function-related proteins with the risk of diabetic nephropathy. Semsitivity analyses were conducted using the Cochran’s Q test and MR-Egger regression intercept. The significance level, as indicated by the P value, was employed as the pivotal metric for interpreting the findings. Result. A total of 90 single nucleotide polymorphisms associated with mitochondrial function-related proteins were meticulously screened as instrumental variables. The inverse variance weighted analysis unveiled a positive causal nexus between mitochondrial glutamate carrier 2, 2,4-dienoyl-CoA reductase mitochondrial levels, 39S ribosomal protein L52 mitochondrial, ATP synthase subunit beta mitochondrial, Serine--tRNA ligase mitochondrial, itochondrial sodium/hydrogen exchanger 9B2, and Esseential MCU regulator mitochondrial, and diabetic nephropathy. Conversely, pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1 mitochondrial exhibited a negative causal relationship with diabetic nephropathy., the MR-Egger intercept test yielded non-multiplicative results (P  >  0.05), affirming the robustness and validity of Mendelian randomization as an effective method for causal inference in this investigation. Furthermore, the reverse Mendelian randomization analysis failed to demonstrate any causal link between diabetic nephropathy and an augmented risk associated with positively identified mitochondrial function-related proteins. Conclusion. Pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1 mitochondrial stands out as an independent protective factor against diabetic nephropathy. The findings bear significant clinical implications, offering pivotal insights into the development of targeted preventive and therapeutic interventions, tailored specifically for combating diabetic nephropathy.