The causal relationship between plasma protein‐to‐protein ratios and type 2 diabetes and its complications: Proteomics mendelian randomization study

Abstract Aim In recent years, proteomics research has surged, with numerous observational studies identifying associations between plasma proteins and type 2 diabetes. However, research specifically focusing on the ratios of plasma proteins in type 2 diabetes remains relatively scarce. Methods This study primarily employed a two‐sample, two‐step Mendelian randomization (MR) approach, leveraging genetic data from several large, publicly accessible genome‐wide association studies, wherein single nucleotide polymorphisms served as proxies for exposures and diseases. Within this framework, we applied two‐sample MR to assess the associations between the 2821 plasma protein‐to‐protein ratios and type 2 diabetes along with its complications and utilized reverse MR to confirm the unidirectionality of these causal relationships. In addition, we employed two‐step MR to investigate the potential mediating role of body mass index in these associations. To augment the robustness of our findings, we systematically implemented a series of sensitivity analyses. Results The results gleaned from the inverse‐variance weighted method elucidated that a cumulative sum of 23 protein‐to‐protein ratios bore a causal nexus with type 2 diabetes across both sample cohorts. With each incremental elevation of 1 standard deviation in the genetically anticipated protein‐to‐protein ratio, the susceptibility to type 2 diabetes oscillated from 0.93 (95% confidence interval: 0.87, 1.00) for the CNTN3/NCSS1 protein level ratio to 1.13 (1.06, 1.22) for the DBNL/NCK2 protein level ratio. Moreover, a tally of eight protein‐to‐protein ratios correlated with a minimum of one complication linked to type 2 diabetes. Diverse sensitivity analyses corroborated the robustness of these observations. Conclusions The outcomes of our investigation unveiled correlations between 23 plasma protein‐to‐protein ratios and type 2 diabetes, with eight of these ratios entwined with complications of type 2 diabetes. These discoveries offer novel perspectives on the diagnosis and management of type 2 diabetes and its associated complications.