Proteogenomic analyses identify coagulation factor XI as a thromboinflammatory mediator of long COVID
Schuermans, A.; Verstraete, A.; Lammi, V.; Nakanishi, T.; Ardissino, M.; Van den Eynde, J.; Sun, B.; Georgakis, M. K.; Van Weyenbergh, J.; Lewandowski, A. J.; Raman, B.; Ollila, H. M.; Burgess, S.; Natarajan, P.; Honigberg, M. C.; Freson, K.; Vanassche, T.; Verhamme, P.
Show abstract
SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. Here, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative (ncases=3,018; ncontrols=994,582). Primary analyses revealed that each unit increase in the log-odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95%CI: 1.08-1.35; P=1.2x10-3). This association was independent of acute COVID-19 severity, robust across genetic instruments and methods, and replicated in external datasets for both venous thromboembolism and long COVID. Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating thromboembolism in long COVID pathogenesis.
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