Network-medicine approach for the identification of genetic association of parathyroid adenoma with cardiovascular disease and type-2 diabetes

Abstract

Primary hyperparathyroidism is caused by solitary parathyroid adenomas (PTAs) in most cases (⁓85%), and it has been previously reported that PTAs are associated with cardiovascular disease (CVD) and type-2 diabetes (T2D). To understand the molecular basis of PTAs, we have investigated the genetic association amongst PTAs, CVD and T2D through an integrative network-based approach and observed a remarkable resemblance. The current study proposed to compare the PTAs-associated proteins with the overlapping proteins of CVD and T2D to determine the disease relationship. We constructed the protein–protein interaction network by integrating curated and experimentally validated interactions in humans. We found the $11$ highly clustered modules in the network, which contain a total of $13$ hub proteins (TP53, ESR1, EGFR, POTEF, MEN1, FLNA, CDKN2B, ACTB, CTNNB1, CAV1, MAPK1, G6PD and CCND1) that commonly co-exist in PTAs, CDV and T2D and reached to network’s hierarchically modular organization. Additionally, we implemented a gene-set over-representation analysis over biological processes and pathways that helped to identify disease-associated pathways and prioritize target disease proteins. Moreover, we identified the respective drugs of these hub proteins. We built a bipartite network that helps decipher the drug–target interaction, highlighting the influential roles of these drugs on apparently unrelated targets and pathways. Targeting these hub proteins by using drug combinations or drug-repurposing approaches will improve the clinical conditions in comorbidity, enhance the potency of a few drugs and give a synergistic effect with better outcomes. This network-based analysis opens a new horizon for more personalized treatment and drug-repurposing opportunities to investigate new targets and multi-drug treatment and may be helpful in further analysis of the mechanisms underlying PTA and associated diseases.