Investigating the genetic effects of metformin-related targets on IgA nephropathy using Mendelian randomization

The role of metformin and its downstream targets in IgA nephropathy (IgAN) remains unclear. In this study, we used Mendelian randomization to explore potential causal links between genetic proxies of metformin targets, plasma proteins, and the risk of IgAN. Data on plasma protein, metformin target genes, and IgAN data were obtained from the IEU OpenGWAS Project. Single-nucleotide polymorphisms (SNPs) associated with metformin target genes and plasma proteins were selected as instrumental variables. We applied a two-sample and two-step Mendelian randomization approach to examine the causal relationships among these variables. Inverse variance weighted analysis revealed that electron transport flavoprotein dehydrogenase (ETFDH) inhibitors were associated with a reduced risk of IgAN (odds ratio [OR] = 0.948, 95% confidence interval [CI]: 0.923-0.973, p < 0.001). A significant causal relationship was identified between ETFDH inhibitors and 592 plasma proteins. Among these, 420 were identified as protective factors. Additionally, 133 plasma proteins were significantly associated with IgAN, of which 78 were identified as risk factors for IgAN. Synaptosome-associated protein 29 was identified as a plasma risk factor for IgAN (OR = 1.118, 95% CI: 1.025-1.218, p = 0.012) and negatively correlated with ETFDH inhibitor use (OR = 0.775; 95% CI, 0.709-0.848; p < 0.001). This protein appeared to mediate the effects of ETFDH inhibitors on the risk of IgAN (total effect: 0.054; mediation ratio: 52.524%). ETFDH may serve as a potential novel target downstream of metformin-associated metabolic pathways.