IDDF2023-ABS-0169 Multi-omics profiling of human liver donors identifies the risks towards post-transplant diabetes mellitus

Background

Posttransplant diabetes mellitus (PTDM) seriously affects the survival and living quality of liver transplantation (LT) patients, but the molecular mechanism remains unclear. Here, we used multi-omics approaches to investigate the genetic and clinical characteristics of PTDM, explored the differences and the connections with type 2 diabetes (T2D), and proposed a new subtype of PTDM.

Methods

We collected a total of 199 donor liver tissues and performed ASA chip, 850K chip, mRNA-seq and miRNA-seq analysis. PTDM was defined according to the American Diabetes Association's diagnostic criteria for diabetes.

Results

PTDM is characterized by a change of the VEGFA-VEGFR2 pathway, which is regulated by both miRNA and methylation in the donor's liver. Recipients in the highest tertiles of donor T2D polygenetic risk scores had the greatest risk of PTDM, with an odds ratio of 3.57 (95%CI=1.31-10.45), compared with recipients in the lowest tertiles (P= 0.015). PTDM and T2D shared common characteristics in cell adhesion molecules pathway, and complement and coagulation cascades pathway. Based on the elastic net model, we identified 18 features, including genetic and clinical factors, that predicted the incidence of PTDM with an AUC of 0.885. Three robust clusters were found in PTDM patients by unsupervised clustering, among which the C3 cluster had the highest infection risk, the slowest tacrolimus metabolism and the lowest survival rate with PI3K-AKT inactivation. We identified 1527 eQTLs, 201481 meQTLs and 2073888 eQTMs associations and developed a web-accessible database for further exploration.

Conclusions

Taken together, these findings reveal that VEGFA-VEGFR2 is regulated by both miRNA and methylation in PTDM patients. VEGFA/PI3K/AKT pathway might be potential therapeutic targets for PTDM.