Genetic Evidence Reveals Causal Effect of Circulating Proteome on Random Glucose: A Mendelian Randomization Study

Random glucose (RG) testing provides greater flexibility and convenience, enabling real-time evaluation of blood glucose levels without the need to consider recent dietary intake. This study was aimed at identifying drug targets using the evidence from circulating proteins associated with RG from genome-wide association studies (GWASs).

Using two-sample Mendelian randomization (MR) with circulating protein data from nine GWAS, we revealed potential causal relationships between these proteins and RG. A framework of sensitivity analyses was performed to assess the robustness and credibility of the evidence.

In the cis-protein quantitative trait loci (pQTLs) and the combined cis/trans-pQTLs analyses, 12 and 31 proteins demonstrated causal effects on RG, respectively. Enrichment analysis revealed that proteins prioritized by cis-MR were enriched in the carbohydrate catabolic process, collagen-containing extracellular matrix, and peptidase regulator activity. For all MR-prioritized proteins, pathways were enriched in those related to the maintenance of location, secretory granule lumen, sulfuric ester hydrolase activity, and regulation of lipolysis in adipocytes. Notably, approximately half of these proteins (including PCSK1, PPY, and VWF) were recognized as druggable or existing drug targets.

This study identified proteins causally linked to RG, emphasizing their potential role in the development of therapeutic interventions for metabolic disorders, particularly those involving glucose regulation.