Genetic Downregulation of Interleukin‐6 Signaling, Coagulation Function, and Risk of Thromboembolic Disease
Journal of the American Heart Association, 2025
Daghlas I., Gill D.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background
Although genetic evidence supports IL‐6 (interleukin‐6) signaling inhibition as protective against atherosclerotic disease, its potential effects on thromboembolic outcomes are not well established. We conducted a Mendelian randomization analysis to investigate the association of genetically proxied IL‐6 signaling inhibition with venous thromboembolism, cardioembolic stroke, and coagulation cascade protein levels.
Methods
IL‐6 signaling inhibition was proxied using the rs2228145 IL6R missense variant, which impairs classical IL‐6 signaling and lowers CRP (C‐reactive protein) levels. Genetic associations with thromboembolic disease outcomes were obtained from genome‐wide association studies of venous thromboembolism (81 190 cases) and cardioembolic stroke (10 804 cases). As atherosclerotic comparator traits, we included coronary artery disease (181 522 cases) and large‐artery atherosclerotic stroke (6399 cases). Genetic associations with 35 coagulation cascade protein levels were obtained from the UK Biobank (n=6218) and deCODE cohorts (n=35 559). Mendelian randomization estimates were derived using the Wald ratio method, scaled per 1‐unit decrease in natural log‐transformed CRP levels.
Results
Genetically proxied IL‐6 signaling inhibition was associated with increased risk of venous thromboembolism (odds ratio [OR], 1.31 [95% CI, 1.16–1.47], P =6.5×10 −6 ) but not with cardioembolic stroke (OR, 1.25 [95% CI, 0.73–2.14], P =0.42). Conversely, protective associations were observed for both coronary artery disease and large‐artery atherosclerotic stroke. Proteomic analyses demonstrated significant reductions in levels of 5 procoagulant and 7 anticoagulant or antifibrinolytic proteins.
Conclusions
These findings suggest that IL‐6 signaling inhibition dysregulates coagulation homeostasis and increases venous thromboembolism risk. Further experimental, translational, and epidemiologic studies are warranted to delineate underlying mechanisms and to evaluate thromboembolic safety in pharmacologic IL‐6 signaling inhibition.