Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomisation analysis

Abstract

AbstractBackground:People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer.Methods:We used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers.Results:We found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE,P =0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship.Conclusions:These findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.Key messages1) There is strong observational evidence that active cancer is associated with venous thromboembolism.2) It is currently unknown whether venous thromboembolism is a risk factor for cancer.3) We applied a bi-directional Mendelian randomisation framework to appraise the causal relationships between genetically-proxied risk of venous thromboembolism and 18 different cancers.4) Overall, there was no clear evidence from Mendelian randomisation that lifetime-elevated risk of venous thromboembolism is causally associated with an increased risk of cancer, or visa versa.