Molecular Determinants of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes Open Access

• 28 loci/proteins associated with VTE recurrence risk.

• The genomic architecture of VTE recurrence risk varies based on the initial clinical presentation.

Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within five years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding. We analysed the genomic architecture of VTE recurrence using data from 6,355 patients across eight cohorts (including 1,775 recurrences), enriched by subgroup analyses, according to sex and clinical manifestation of first VTE, which led to the identification of 28 molecular markers. Through genome-wide association studies, we identified one locus associated with VTE recurrence: GPR149/MME. Among all variants known to be associated with first VTE, KNG1 and FGG were associated with recurrence. Additionally, Mendelian Randomization analyses identified seven proteins as risk factors for recurrence: elevated plasma levels of coagulation factor XI, coagulation factor VIII, von Willebrand factor, BGAT and GOLM2; decreased levels of PCSK9 and pro-IL16. Subgroup analyses revealed 18 molecular determinants associated with VTE recurrence, with notable differences between subgroups. For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated in pulmonary embolism patients (Hazard Ratio (HR)=3.13, P=5.9×10-11) but showed no effect in deep vein thrombosis patients (HR=0.91, P=0.72). These findings emphasize the role of specific genetic loci and protein pathways in influencing VTE recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.