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Coagulation & its Disorders
Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism
Ferrata Storti Foundation
Haematologica 2020 Volume 105(7):1963-1968
Benedikte Paulsen,1 Hanne Skille,1 Erin N. Smith,2 Kristian Hveem,3,4,5 Maiken E. Gabrielsen,4,5 Sigrid K. Brækkan,1,6 Frits R. Rosendaal,1,7 Kelly A. Frazer,1,2 Olga V. Gran1 and John-Bjarne Hansen1,6
1K.G. Jebsen Thrombosis Research and Expertise Center (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway; 2Department of Pediatrics and Rady’s Children’s Hospital, University of California, San Diego, La Jolla, CA, USA; 3St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway;
4HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; 5K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway; 6Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway and 7Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
ABSTRACT
Venous thromboembolism (VTE) is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of VTE, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of VTE. Cases with incident VTE (n=640) and a randomly selected age-weighted sub-cohort (n=3,734) were derived from a population-based cohort (the Tromsø study). Cox-regression was used to estimate hazard ratios (HR) with 95% confi- dence intervals (CI) for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7, 95% CI: 1.2-2.3) increased risk of VTE compared to non-carriers. Cancer patients homozygous for the FGG variant had a two- fold (HR 2.0, 95% CI: 1.1-3.6) higher risk of VTE than cancer patients with- out the variant. Moreover, the six-months cumulative incidence of VTE among cancer patients was 6.4% (95% CI: 3.5-11.6) in homozygous carriers of FGG and 3.1% (95% CI: 2.3-4.7) in those without risk alleles. A synergis- tic effect was observed between rs2066865 and active cancer on the risk of VTE (synergy index: 1.81, 95% CI: 1.02-3.21, attributable proportion: 0.43, 95% CI: 0.11-0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded a synergistic effect on the risk of VTE.
Introduction
Venous thromboembolism (VTE), a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disease associated with sub- stantial short- and long-term morbidity and mortality.1,2 The incidence of VTE is 1-2 in 1,000 people/ year, and it increases steeply with age.3 Malignant disease is associated with a four- to seven-fold increased risk of VTE, and 20-25% of all first lifetime VTE-events are cancer-related.4,5 VTE, particularly in cancer, leads to pro- longed and more frequent hospitalizations, and has a substantial impact on quality of life.6,7 Complications of VTE, such as recurrence, post-thrombotic syndrome and treatment-related bleeding, occur more frequently in cancer patients,6,8,9 and the risk of death is higher in cancer patients with than without VTE.10,11
Family and twin studies suggest that VTE is highly heritable, and likely results from an interplay between inherited and environmental factors.12,13 Fibrinogen, the precursor of fibrin, is an essential component in the final stage of the coagulation cascade. The fibrinogen molecule has three subunits called Aα, Bβ and g, which occur in pairs for a total number of six subunits. The g chain, transcribed from the
Correspondence:
BENEDIKTE PAULSEN
benedikte.paulsen@uit.no
Received: April 11, 2019. Accepted: October 3, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2019.224279
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/7/1963
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