Venous thromboembolism occurs frequently in
cancer patients. Two variants in the
factor 5 gene (F5), rs6025 encoding for the
factor V Leiden mutation R506Q, and rs4524 encoding K858R, have been found to be associated with
venous thromboembolism. We assessed the joint effect of active
cancer and these two F5 variants on
venous thromboembolism risk in a case-cohort study. Cases with a first
venous thromboembolism (n=609) and a randomly selected age-weighted cohort (n=1,691) were sampled from the general population in Tromsø, Norway.
Venous thromboembolism was classified as
cancer-related if it occurred in the period 6 months before to 2 years after a diagnosis of
cancer. Active
cancer was associated with an 8.9-fold higher risk of
venous thromboembolism (95% CI 7.2-10.9). The risk of
cancer-related
venous thromboembolism was 16.7-fold (95% CI 9.9-28.0) higher in subjects heterozygous for rs6025 compared with non-carriers of this variant without active
cancer. In subjects with active
cancer the risk of
venous thromboembolism was 15.9-fold higher (95% CI 9.1-27.9) in those with one risk allele at rs4524, and 21.1-fold (95% CI 12.4-35.8) higher in those with two risk alleles compared with non-carriers without active
cancer. A synergistic interaction was observed between active
cancer and
factor V Leiden (relative excess risk due to interaction 7.0; 95% CI 0.5-14.4) and rs4524 (relative excess risk due to interaction 15.0; 95% CI 7.5-29.2). The incidence of
venous thromboembolism during the initial 6 months following a diagnosis of
cancer was particularly high in subjects with risk alleles at these loci. This implies that the combination of
cancer and F5 variants synergistically increases
venous thromboembolism risk.