Shared immune-inflammatory gene networks and drug prediction in polycystic ovary syndrome and type 2 diabetes...

Polycystic ovary syndrome (PCOS) is associated with an increased risk of type 2 diabetes mellitus (T2DM), and the risk of PCOS increases in patients with T2DM of reproductive age. The bidirectional link between PCOS and T2DM has been confirmed through experimental and epidemiological evidence; however, the genetic factors that contribute to deeper insights into the shared pathogenesis of these two diseases remain unclear. We aimed to identify shared immune- and inflammation-related genes and pathways in PCOS and T2DM, further explore the molecular mechanisms in developing this comorbidity, and predict drugs with potential effects to develop novel therapeutic strategies.

We obtained microarray expression profiling datasets (GSE34526 and GSE25724) of PCOS and T2DM from the Gene Expression Omnibus (GEO) database. The differential expression genes (DEGs) between disease and control groups were identified and analyzed via the R package "limma" following data preprocessing. The R package "clusterProfiler" was applied to conduct Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses. Hub genes were identified from the protein-protein interaction (PPI) network using the Molecular Complex Detection (MCODE) and cytoHubba plug-ins of Cytoscape. Transcription factor (TF)-hub and miRNA-hub gene regulatory networks were constructed and visualized using Cytoscape. The Drug-Gene Interaction Database (DGIdb) was used to predict prospective drugs targeting hub genes. In addition, hub genes were verified by RT-qPCR.

A total of 239 common DEGs, including 140 upregulated genes and 99 downregulated genes, were discovered. These common DEGs were primarily associated with immune regulation and inflammatory processes. Moreover, ITGAM, ITGB2, SPI1, C1QB, CCR5, C3AR1, LY86, AIF1, and IRF8 were identified as hub genes and the RT-qPCR results showed significant differences. These hub genes were predominantly related to the regulation of neutrophil degranulation (ITGAM, ITGB2, and SPI1), dendritic cell chemotaxis (CCR5 and SPI1), follicular B cell differentiation (SPI1 and IRF8), synapse pruning (ITGAM and C1QB), integrin αM-β2 complex (ITGAM and ITGB2), the regulation of prostaglandin-E synthase activity (ITGAM and ITGB2), Staphylococcus aureus infection (ITGAM, ITGB2, C1QB, and C3AR1) and pertussis (IRF8). Finally, we predicted 19 TFs, 170 miRNAs, and 40 potential therapeutic drugs interacting with hub genes.

We identified nine hub genes and related gene regulatory networks and discussed novel perspectives on the roles of immunity and inflammation in patients with PCOS and T2DM. Moreover, maraviroc, cenicriviroc, PF-04634817 (targeting CCR5), butein (targeting ITGB2), dimethyl sulfoxide (targeting ITGAM), and rovelizumab (targeting both ITGB2 and ITGAM) are potential therapeutic drugs. However, these findings require validation through further clinical and experimental studies.