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

Abstract

Background: 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.

Keywords: Mendelian randomisation; deep vein thrombosis; genetic epidemiology; malignancy; pulmonary embolus.

Figure 1

Forest plot showing estimates from Mendelian randomisation inverse variance weighted estimates (MR-IVW) of the effect of genetically-proxied risk of venous thromboembolism (VTE) as an exposure on 18 cancers as outcomes: results are represented as the odds ratio (OR) and 95% confidence interval (CI) for each cancer per log-odds increase in risk of VTE. Nominal P values (P), false discovery corrected P values (FDR-P) and heterogeneity P values for Cochrane’s Q statistic (het-P) are shown.

Figure 2

Mendelian randomisation sensitivity analyses of genetically-proxied risk of venous thromboembolism (VTE) as an exposure and four cancers (outcomes) which showed an association (P≤0.05) in the MR-IVW analysis (pancreatic, ovarian, endometrial and oral cancer). Left plot [A] shows sensitivity analyses including all SNPs. Right plot [B] shows sensitivity analyses with rs687289 removed. Results are represented as the odds ratio (OR) and 95% confidence interval (CI) for each cancer per log-odds increase in genetic risk of VTE.

Figure 3

Mendelian randomisation Wald ratios for association between [A] venous thromboembolism (VTE), proxied by Factor V Leiden only), and risk of 18 cancers and [B] VTE, proxied by Prothrombin G20210A only, and risk of 12 cancers. Results are represented as the odds ratio (OR) and 95% confidence interval (CI) for each cancer per log-odds increase in genetic risk of VTE. Nominal P values (P) and false discovery corrected P values (FDR-P) are shown. NA indicates cancers for which the Prothrombin G20210A variant was not available in the GWAS summary data.

Figure 4

Forest plot showing estimates from Mendelian randomisation (MR) estimates of the effect of genetic risk of 18 cancers as exposures on venous thromboembolism (VTE), as an outcome. The MR inverse variance weighted estimate is shown for all cancers except marginal zone lymphoma, where the Wald ratio is shown as only a single instrumental variable was available. Results are represented as the odds ratio (OR) and 95% confidence interval (CI) for VTE per log-odds increase in genetic risk of each cancer. Nominal P values (P), false discovery corrected P values (FDR-P) and heterogeneity P values for Cochrane’s Q statistic (het-P) are shown.