Therapeutic Targets for Diabetic Kidney Disease: Proteome-Wide Mendelian Randomization and Colocalization Analyses

Abstract

At present, safe and effective treatment drugs are urgently needed for diabetic kidney disease (DKD). Circulating protein biomarkers with causal genetic evidence represent promising drug targets, which provides an opportunity to identify new therapeutic targets. Summary data from two protein quantitative trait loci studies are presented, one involving 4,907 plasma proteins data from 35,559 individuals and the other encompassing 4,657 plasma proteins among 7,213 European Americans. Summary statistics for DKD were obtained from a large genome-wide association study (3,345 cases and 2,372 controls) and the FinnGen study (3,676 cases and 283,456 controls). Mendelian randomization (MR) analysis was conducted to examine the potential targets for DKD. The colocalization analysis was used to detect whether the potential proteins exist in the shared causal variants. To enhance the credibility of the results, external validation was conducted. Additionally, enrichment analysis, assessment of protein druggability, and the protein-protein interaction networks were used to further enrich the research findings. The proteome-wide MR analyses identified 21 blood proteins that may causally be associated with DKD. Colocalization analysis further supported a causal relationship between 12 proteins and DKD, with external validation confirming 4 of these proteins, and TGFBI was affirmed through two separate group data sets. These results indicate that targeting these four proteins could be a promising approach for treating DKD, and warrant further clinical investigations.

Figure 1

Overview of the study design in our MR and colocalization study.

Figure 2

The 21 significant potential drug targets in two independent DKD case-control cohorts. The y axis shows the protein name. The x axis shows the OR. The error bars represent the DKD OR per 1 SD increase in protein expression, calculated using the Wald ratio (if 1 SNP) or inverse variance weighted method (if >1 SNP) and corrected for the number of genes tested. nsnp, number of SNP.

Figure 3

GO enrichment analysis of 12 identified proteins for treatment of DKD. Significantly enriched GO terms of similar expressed proteins in DKD.

Figure 4

Key signaling pathways of 12 identified proteins associated of DKD. The x axis represents gene ratio, and the y axis represents different biological pathways. The size of the circle represents protein count. Different colors of circles represent different P values.

Figure 5

Interaction between current DKD medications targets and identified potential drug targets.