Analysis of the Genetic Comorbid Mechanisms of Type 2 Diabetes, Alzheimer's Disease, and Hypertension Using Network Modularization.

BACKGROUND

Type 2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and hypertension (HTN) tend to be comorbidities and mutually influence each other; however, the mechanisms underlying their association remain unclear. This study was aimed at identifying genes associated with susceptibility to these three diseases and their mechanisms of action using integrated network modularization analysis.

METHODS

The transcriptome data of T2DM, AD, and HTN were downloaded from the GEO database to identify the differentially expressed genes (DEGs), and the coexpression modules of each disease were detected by WGCNA. Z summary algorithm was used to identify the common modules of three diseases, and the driver genes of their comorbidity were identified by flow centrality (FC) and shortest distance indexes. Gene set enrichment analysis (GSEA) was performed to define the biological functions and pathways for each module and driver genes. The HPA database and CIBERSORT method were used to analyze the mechanisms of the shared key genes from the types of single cells and immune infiltration analysis.

RESULTS

Based on the 343 overlapping DEGs that were identified, four common modules between AD, T2DM, and HTN were identified using Z summary. GSEA revealed that the DEGs were mainly involved in the MAPK and mTOR signaling pathways. Eight key genes (ACTN4, BGN, PRELP, TSFM, UBC, ELAVL1, NRF1, and SUMO2) related to the comorbidities AD, T2DM, and HTN were identified by integrating the shared genes at the levels of DEGs, common modules, and FC-based driver genes. As potential biomarkers, the expression of these key genes was significantly different between the three disease groups, and they were mainly expressed in endothelial cells, Langerhans cells, smooth muscle cells, and T cells. Immune infiltration analysis revealed that five different types of immune cells were related to these three diseases, including T-regs and nonclassical monocytes.

CONCLUSIONS

Common modules between T2DM, AD, and HTN and eight key susceptibility genes were identified, which may reflect the underlying mechanism of the comorbidity of T2DM, AD, and HTN. These results provide insights for the development of clinical therapies for these diseases.