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Genetic Downregulation of Interleukin-6 Signaling, Coagulation Function, and Risk of Thromboembolic Disease.

Iyas Daghlas·Dipender Gill
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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.

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HumansInterleukin-6Mendelian Randomization AnalysisBlood CoagulationSignal TransductionVenous ThromboembolismRisk FactorsGenome-Wide Association StudyDown-RegulationMaleC-Reactive ProteinFemaleRisk AssessmentReceptors, Interleukin-6Genetic Predisposition to DiseaseEmbolic StrokePolymorphism, Single NucleotideMiddle Agedcardioembolic strokecoagulationinterleukin‐6proteomicsvenous thromboembolismJournal ArticleResearch Support, Non-U.S. Gov't

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Iyas Daghlas, Dipender Gill. 2025-12-11. Genetic Downregulation of Interleukin-6 Signaling, Coagulation Function, and Risk of Thromboembolic Disease.. https://doi.org/10.1161/jaha.125.043972

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