Genetic insights into cytokine-thrombosis cross-talk: an integrated multi-omics network analysis

The mechanisms shared and unique to thrombotic diseases (TDs) remain unclear. This study explores the causal relationships between inflammatory cytokines and TDs via multi-omics integration to identify targeted therapeutic alternatives.

We conducted two-sample Mendelian randomization (MR) using three genetic instruments to evaluate the causal effects of 47 cytokines on 13 TD traits. Findings were validated through colocalization, replication, and transcriptomic analyses. Two-step MR assessed mediation effects of 1400 metabolites and 731 immune cells. Druggability and infection-related pleiotropy of TD-associated cytokines were systematically evaluated.

Primary MR identified 86 cytokine-TD correlated pairs, with 21 pairs providing acceptable evidence support, meriting their designation as hub pairs for further analysis. Colocalization evidence emerged for two pairs, whereas replication consistency was robust. Five of the 15 cytokine gene-TD pairs revealed differential expression, aligning with the MR effects. Mediation analyses showed five metabolites and immune cell subtypes modulating cytokine-TD pathways. Four cytokines exhibited therapeutic promise for thrombosis, whereas six showed dual effects on TDs and infections.

Our integrated analysis reveals shared and autonomous mechanisms governing inflammatory-thrombotic interactions and identifies a cytokine-mediated therapeutic target that may avoid bleeding complications linked to standard antithrombotic therapy.