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. 2024 Feb 1;53(1):dyad170.
doi: 10.1093/ije/dyad170.

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

Naomi Cornish  1   2 , Philip Haycock  3 , Hermann Brenner  4   5   6 , Jane C Figueiredo  7 , Tessel E Galesloot  8 , Robert C Grant  9 , Mattias Johansson  10 , Daniela Mariosa  10 , James McKay  10 , Rish Pai  11 , Andrew J Pellatt  12 , N Jewel Samadder  13 , Jianxin Shi  14 , Florian Thibord  15 , David-Alexandre Trégouët  16 , Catherine Voegele  10 , Chrissie Thirlwell  2   17 , Andrew Mumford  1 , Ryan Langdon  3 ; InterLymph Consortium, INVENT-MVP Consortium
Affiliations

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

Naomi Cornish et al. Int J Epidemiol. .

Abstract

Background: People with cancer experience high rates of venous thromboembolism (VTE). Risk of subsequent cancer is also 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 bidirectional Mendelian randomization analyses to estimate causal associations between genetic liability to VTE and risk of 18 different cancers.

Results: We found no conclusive evidence that genetic liability to VTE was causally associated with an increased incidence of cancer, or vice versa. We observed an association between liability to VTE and pancreatic cancer risk [odds ratio for pancreatic cancer: 1.23 (95% confidence interval: 1.08-1.40) per log-odds increase in VTE risk, P = 0.002]. However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence to suggest a causal relationship.

Conclusions: These findings do not support the hypothesis that genetic liability to 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 synthesize evidence for these mechanisms.

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

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Conflict of interest statement

R.C.G. is an advisory or honorary for Astrazeneca, Eisai and Knight Therapeutics and is in receipt of a Graduate Scholarship from Pfizer. No other conflicts of interest declared.

Figures

Figure 1.
Figure 1.
Forest plot showing estimates from Mendelian randomization inverse variance-weighted estimates of the effect of genetic liability to venous thromboembolism as an exposure on 18 cancers as outcomes. CI, confidence interval; FDR-P, false-discovery corrected P-value; het-P, heterogeneity P-value for Cochran’s Q statistic; OR, odds ratio; VTE, venous thromboembolism
Figure 2.
Figure 2.
Mendelian randomization sensitivity analyses of genetic liability to venous thromboembolism as an exposure and risk of four cancers (pancreatic, ovarian, endometrial and oral cancer) which showed an association (P ⩽0.05) in the MR-IVW analysis. (A) shows sensitivity analyses including all SNPs. (B) shows sensitivity analyses with rs687289 removed. CI, confidence interval; FDR-P, false-discovery corrected P-value; het-P, heterogeneity P-value for Cochran’s Q statistic; MR-IVW, Mendelian randomization inverse variance-weighted estimates; OR, odds ratio; SNP, singlenucleotide polymorphism; VTE, venous thromboembolism
Figure 3.
Figure 3.
Mendelian randomization Wald ratios for association between (A) liability to VTE, proxied by Factor V Leiden only, and risk of 18 cancers; and (B) liability to VTE, proxied by Prothrombin G20210A only, and risk of 12 cancers. NA indicates cancers for which the Prothrombin G20210A variant was not available in the genome-wide association study summary data. CI, confidence interval; FDR-P, false-discovery corrected P-value; OR, odds ratio; VTE, venous thromboembolism
Figure 4.
Figure 4.
Forest plot showing estimates from Mendelian randomization analyses of the effect of genetic liability to 18 cancers as exposures on risk of venous thromboembolism as an outcome. The Mendelian randomization inverse variance-weighted estimates are shown for all cancers except marginal zone lymphoma, where the Wald ratio is shown, as only a single instrumental variable was available. CI, confidence interval; FDR-P, false-discovery corrected P-value; het-P, heterogeneity P-value for Cochran’s Q statistic; OR, odds ratio; VTE, venous thromboembolism
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