Abstract

Objective Autoimmune diseases (ADs) markedly elevate venous thromboembolism (VTE) risk, yet the shared genetic architecture and tissue-specific regulatory mechanisms of this “Autoimmune-Thrombotic Axis” remain poorly defined. We aimed to characterize the genomic landscape of immunothrombosis to identify causal links and therapeutic targets.

Approach and Results We integrated large-scale GWAS data for VTE and 16 ADs using a multi-omics framework, including pleiotropy scanning, local genetic correlation, and summary-based Mendelian randomization (SMR). We identified 21 Immunothrombotic Shared Loci (ISLs) and 274 pleiotropic genes enriched in complement and coagulation cascades. Mendelian randomization (MR) analysis revealed a robust causal effect of genetically predicted systemic lupus erythematosus (SLE) on VTE risk (OR = 1.018, 95% CI: 1.008-1.029, P = 0.0003). Mechanistically, IL6R and PLCL1 emerged as central mediators with distinct tissue-specific regulatory partitioning. Colocalization confirmed that shared genetic susceptibility is primarily driven by expression in arterial tissues (aorta and coronary) rather than exclusively in immune cells. Furthermore, the lead SNP rs4129267 was identified as a potential predictor for VTE in rheumatoid arthritis patients, and drug prioritization nominated TNF inhibitors as promising candidates for mitigating thrombotic burden.

Conclusion This study establishes the first genomic atlas of the autoimmune-thrombotic axis, demonstrating that vasculature-specific gene regulation drives immunothrombosis. These findings provide a biological basis for VTE risk stratification and suggest that genotype-guided therapy may optimize vascular outcomes in AD patients.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This project is supported by the National Natural Science Foundation of China (No. 82504843 and 82570245). We would like to express our gratitude to the researchers and consortia that made their GWAS summary statistics publicly available, enabling this work.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The data supporting this study are derived from publicly available sources, which have been detailed in the reference list of the article.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data Availability

This study is a secondary analysis of publicly available data. All genome-wide association study (GWAS) summary statistics used in this work were obtained from public databases and consortia (e.g., FinnGen, GWAS Catalog, eQTLGen, GTEx). The specific sources are detailed in the Methods section and Table S1. No new primary data were generated.

SUMMARY OF ABBREVIATIONSADAutoimmune DiseaseAPSAntiphospholipid SyndromeASAnkylosing SpondylitisCDCrohn’s DiseaseCPASSOCCross-Phenotype AssociationDMPMDermatomyositis/PolymyositiseQTLExpression Quantitative Trait LociFDRFalse Discovery RateFLSFibroblast-like SynoviocytesFUMAFunctional Mapping and Annotation of Genetic AssociationsGBSGuillain-Barré SyndromeGDGraves’ DiseaseGOGene OntologyGTExGenotype-Tissue Expression projectGWASGenome-Wide Association StudyHDLHigh-Definition LikelihoodHEIDIHeterogeneity in Dependent InstrumentsHTHashimoto’s ThyroiditisIBDInflammatory Bowel DiseaseIVWInverse Variance WeightedKEGGKyoto Encyclopedia of Genes and GenomesLAVALocal Analysis of [co]Variant AssociationLDLinkage DisequilibriumLDSCLinkage Disequilibrium Score RegressionMAGMAMulti-marker Analysis of GenoMic AnnotationMACEMajor Adverse Cardiovascular EventsMGMyasthenia GravisMRMendelian RandomizationMSMultiple SclerosisMSigDBMolecular Signatures DatabaseNETsNeutrophil Extracellular TrapsNMONeuromyelitis OpticaPLACOPleiotropic Analysis under Composite Null HypothesisPP.H4Posterior Probability for Hypothesis 4RARheumatoid ArthritisSMRSummary-based Mendelian RandomizationSLESystemic Lupus ErythematosusSNPSingle-Nucleotide PolymorphismSSSjögren’s SyndromeSSCSystemic SclerosisT1DType 1 DiabetestfQTLTranscription Factor Quantitative Trait LocusUCUlcerative ColitisVTEVenous Thromboembolism1KG1000 Genomes Project