RNA sequencing-derived gene co-expression and drug-gene interaction analysis reveal STAT1 as a potential therapeutic target in thrombotic antiphospholipid syndrome

Objective Thrombotic primary antiphospholipid syndrome (PAPS) pathogenesis remains undefined, and recurrent thrombosis may occur despite adequate anticoagulation treatment. Identifying disease-specific molecular pathways and regulators can help in the discovery of novel therapeutic targets. Herein, we examine gene co-expression networks and potential druggable targets in thrombotic PAPS. Methods We analyzed a whole-blood RNA-sequencing dataset from 62 well-characterized patients with thrombotic PAPS (40% with recurrent thrombosis), and 29 age/sex-matched healthy controls(HCs). Weighted Gene Co-expression Network Analysis (WGCNA) was performed to identify gene modules associated with PAPS, followed by enrichment analysis. Drug-gene interaction analysis of hub regulators within the identified networks was applied. Genes were classified based on target drug annotation and priority categories (low/medium/high). Results WGCNA of whole-blood transcriptome of thrombotic PAPS and HCs, which included 8,190 expressed genes, identified five co-expression modules, two of which correlated with PAPS: the yellow, consisted of 42 genes enriched in immune-related functions, and the brown comprised 144 genes with a regulatory signature enriched in transcription activation pathways. A merged module demonstrated enhanced correlation with PAPS compared with HCs (r=0.221, p=0.035). Both yellow and brown, and merged module, were co-regulated by Transducer and Activator of Transcription 1 ( STAT1 ), which emerged as a central hub gene. STAT1 was also present in 5 of 6 immune-related pathways. In drug-gene interaction analysis, STAT1 was among the four highly-ranked genes, and displayed many interactions and strong pharmacological support. Conclusion STAT1 is identified as a central regulator of gene expression networks in PAPS, integrating both immune-related and regulatory processes. Assessment of pharmacological target availability revealed STAT1 as a promising treatment target.