Beyond the Very Important Pharmacogenes (VIPs): Uncovering Shadow Pharmacogenes in the Human Drug Response Network.

Understanding the molecular determinants of interindividual drug response variability remains a major challenge in pharmacogenomics. Very Important Pharmacogenes (VIPs), as defined by PharmGKB, represent genes with well-established roles in drug metabolism and efficacy. However, their activity occurs within complex molecular networks that extend beyond direct pharmacogenetic associations. We constructed a VIP-centered subnetwork and applied network topology analyses, including shortest path, signal propagation, and degree centrality, to identify key nodes mediating VIP interactions. Functional enrichment, transcription factor (TF) association, and drug-gene interaction analyses were subsequently performed to characterize the biological and pharmacological context of these networks. Our results revealed a dense VIP interactome enriched in metabolic, endocrine, and signaling pathways. Notably, we identified a subset of highly connected non-VIP genes that frequently bridge canonical VIPs, termed shadow VIPs. These genes, often encoding transcriptional regulators, such as