Investigating associations between JAK inhibition and venous thromboembolism by systematic mining of large-scale...

Janus kinase inhibitors (JAKi) have been associated with an increased risk of venous thromboembolism (VTE) limiting the use of JAKi-based therapy. To improve risk stratification and drug development, it is crucial to understand the implication of dysregulated JAK-Signal Transducers and Activators of Transcription (STAT) signaling in the pathogenesis of VTE. The objective of this study is to clarify the putative genomic vulnerability to dysregulated JAK-STAT signaling in VTE through systematic mining of large-scale datasets generated from studies comparing VTE patients with healthy controls. Particularly, we assess the representation of entities of the JAK-STAT signaling pathway including STAT target genes among sets of miRNA, mRNA, and proteins differentially abundant in VTE patients, and we explore the putative cumulative genetic association of JAK-STAT signaling gene sets to VTE. Genes related to the JAK-STAT pathway were found significantly altered in VTE patients compared to healthy controls, indicating that genes under transcriptional control of STAT may be dysregulated in VTE. In support of this notion, we find a significant overrepresentation of predicted STAT target genes among genes downregulated in VTE patients, and promoter sequences of differentially regulated genes were significantly enriched with STAT transcription factor binding site motifs. Further linking STAT signaling to the molecular signature of VTE, genes targeted by miRNAs differentially regulated in patients are significantly enriched with STAT target genes and genes acting in the JAK-STAT signaling pathway. Together, our findings indicate that disruptions in the JAK-STAT pathway contribute to the molecular profile of VTE. This offers hope for identifying ways to interact with the JAK-STAT pathway that do not carry the risk of VTE.