Novel Protein Biomarkers and Therapeutic Targets for Type 1 Diabetes and Its Complications: Insights from Summary-Data-Based Mendelian Randomization and Colocalization Analysis

Abstract

Millions of patients suffer from type 1 diabetes (T1D) and its associated complications. Nevertheless, the pursuit of a cure for T1D has encountered significant challenges, with a crucial impediment being the lack of biomarkers that can accurately predict the progression of T1D and reliable therapeutic targets for T1D. Hence, there is an urgent need to discover novel protein biomarkers and therapeutic targets, which holds promise for targeted therapy for T1D. In this study, we extracted summary-level data on 4907 plasma proteins from 35,559 Icelanders and 2923 plasma proteins from 54,219 UK participants as exposures. The genome-wide association study (GWAS) summary statistics on T1D and T1D with complications were obtained from the R9 release results from the FinnGen consortium. Summary-data-based Mendelian randomization (SMR) analysis was employed to evaluate the causal associations between the genetically predicted levels of plasma proteins and T1D-associated outcomes. Colocalization analysis was utilized to investigate the shared genetic variants between the exposure and outcome. Moreover, transcriptome analysis and a protein-protein interaction (PPI) network further illustrated the expression patterns of the identified protein targets and their interactions with the established targets of T1D. Finally, a Mendelian randomization phenome-wide association study evaluated the potential side effects of the identified core protein targets. In the primary SMR analysis, we identified 72 potential protein targets for T1D and its complications, and nine of them were considered crucial protein targets. Within the group were five risk targets and four protective targets. Backed by evidence from the colocalization analysis, the protein targets were classified into four tiers, with MANSC4, CTRB1, SIGLEC5 and MST1 being categorized as tier 1 targets. Delving into the DrugBank database, we retrieved 11 existing medications for T1D along with their therapeutic targets. The PPI network clarified the interactions among the identified potential protein targets and established ones. Finally, the Mendelian randomization phenome-wide association study corroborated MANSC4 as a reliable target capable of mitigating the risk of various forms of diabetes, and it revealed the absence of adverse effects linked to CTRB1, SIGLEC5 and MST1. This study unveiled many protein biomarkers and therapeutic targets for T1D and its complications. Such advancements hold great promise for the progression of drug development and targeted therapy for T1D.

Keywords: GWAS; Mendelian randomization; plasma proteins; therapeutic targets; type 1 diabetes.

Figure 1

Study design for identification of potential protein biomarkers and therapeutic targets for T1D and its associated complications. UKBPPP, UK Biobank Pharma Proteomics Project; T1D, type 1 diabetes; P_fdr, corrected p-value; HEIDI, Heterogeneity in Dependent Instruments; PPH4, posterior probability of hypothesis 4; MR-PheWAS, MR phenome-wide association study [14,15].

Figure 2

Volcano plots of the SMR results between plasma proteins (crucial targets) and T1D−associated outcomes. (A) The exposures were 4907 plasma proteins from the deCODE cohort, and the outcome was T1D; (B) the exposures were 2923 plasma proteins from the UKBPPP cohort, and the outcome was T1D; (C) the exposures were 4907 plasma proteins from the deCODE cohort, and the outcome was T1D with ophthalmic complications; (D) the exposures were 2923 plasma proteins from the UKBPPP cohort, and the outcome was T1D with ophthalmic complications. Red dots represent risk protein targets, green dots represent protective protein targets, and blue dots represent neutral protein targets. Protein targets exhibiting a significant causal association (corrected p-value < 0.05 and p-value of HEIDI test > 0.01) with a T1D−associated outcome are labeled.

Figure 3

Volcano plots of the SMR results between plasma proteins (crucial targets) and T1D−associated outcomes. (A) The exposures were 4907 plasma proteins from the deCODE cohort, and the outcome was T1D with coma; (B) the exposures were 2923 plasma proteins from the UKBPPP cohort, and the outcome was T1D with coma; (C) the exposures were 4907 plasma proteins from the deCODE cohort, and the outcome was T1D with renal complications; (D) the exposures were 2923 plasma proteins from the UKBPPP cohort, and the outcome was T1D with renal complications; (E) the exposures were 4907 plasma proteins from the deCODE cohort, and the outcome was T1D with other complications; (F) the exposures were 2923 plasma proteins from the UKBPPP cohort, and the outcome was T1D with other complications. Red dots represent risk protein targets, green dots represent protective protein targets, and blue dots represent neutral protein targets. Protein targets exhibiting a significant causal association (corrected p-value < 0.05 and p-value of HEIDI test > 0.01) with a T1D−associated outcome are labeled.

Figure 4

Results of SMR analysis between plasma proteins (crucial targets) and T1D-associated outcomes (T1D and T1D with ophthalmic complications). (Only protein targets demonstrating significant causal associations with outcomes in both the deCODE and UKBPPP cohorts are presented. Red represents significant results of colocalization analysis.)

Figure 5

Results of SMR analysis between plasma proteins (crucial targets) and T1D-associated outcomes (T1D with coma, T1D with renal complications and T1D with other complications). (Only protein targets demonstrating significant causal associations with outcomes in both the deCODE and UKBPPP cohorts are presented. Red represents significant results of colocalization analysis.)

Figure 6

The expression patterns of the corresponding genes of 9 identified crucial protein targets in a microarray dataset. (A) The heatmap of the corresponding genes of 9 identified protein targets detected between the T1D and control groups. Red and blue grids represent up- and downregulated genes, respectively. (B–J) The expression differences in the 9 genes between the two groups.

Figure 7

Interactions between current T1D medication targets and identified potential protein targets.

Figure 8

Manhattan plots for MR phenome-wide association study of MANSC4, CTRB1 SILEC5 and MST1. A dot represents a disease or trait.