Nearly half of all venous thromboembolism (VTE) events – in addition to 61.7% of unprovoked VTEs – can be attributed to established prothrombotic genotypes, according to a population-based cohort study published in Thrombosis and Haemostasis. Existing research into the link between prothrombotic genotypes and VTEs within the population has previously been limited.
In this study, investigators led by Line Holted Evensen, PhD, of UiT The Arctic University of Norway, examined the associations between established prothrombotic genotypes and the proportion of VTEs and unprovoked VTEs in a general population using data from two Norwegian population-based cohort studies. Data were derived from the fourth survey of the Tromsø Study (Tromsø 4, 1994-1995), in which 77% of the population of inhabitants ages 25 and older participated, and the second survey of the Nord-Trøndelag Health Study (HUNT 2, 1995-1997), which included data from 71% of inhabitants ages 20 and older.
Participants in the Tromsø Study were followed through December 31, 2012, while follow-up ended in the HUNT study on December 31, 2008.
Investigators discovered 1,493 cases of an incident VTE. They randomly selected 13,072 people without a previous VTE to serve as the sub-cohort.
Patients with a VTE incident had higher mean age, body mass index, systolic blood pressure, and prevalence of arterial cardiovascular disease and diabetes than those without a VTE incident.
Researchers identified 17 single nucleotide polymorphisms (SNPs) that were associated with VTE based on past research and used DNA samples to genotype participants for the SNPs. Six SNPs were significantly associated with VTE: rs1799963 (prothrombin), rs2066865 (fibrinogen gamma), rs6025 (factor V Leiden [FVL]), rs2289252 (factor 11), rs2036914 (factor 11), and rs8176719 (ABO). ABO was associated with the greatest proportion of cases at 18.9% (95% CI 10.8-26.4) followed by factor 11, which was associated with 14.3% of cases (95% CI 1.4-26.7).
Using a six SNP model, investigators determined a population attributable fraction (PAF) of 45.3% for all VTEs. The PAF had a “stepwise” increase as each SNP was added “one-by-one in ranked order,” until a total of five SNPs were added.
Researchers noted that 61.7% of the unprovoked VTE events could be attributed to established prothrombotic genotypes (95% CI 19.6-89.3), which “highlights the need for unraveling novel genetic or environmental risk factors for unprovoked VTE,” they wrote.
While examining the data further, researchers reported that deep vein thrombosis (DVT) had a higher cumulative PAF of 52.9% compared with 33.8% for pulmonary embolism. The difference was primarily driven by a higher PAF for DVT for ABO and FVL.
VTE events were also associated with established prothrombotic genotypes in a larger proportion of younger patients: 66% of younger patients could attribute the VTE to genotype compared to 25% in those ages 70 and older.
“Analyses stratified by age revealed that PAFs were higher among those aged <70 years for rs8176719 (ABO, 28.7% vs. 10.6%), rs2036914 (factor 11, 20.4% vs. 9.5%), and rs2066865 (fibrinogen gamma, 11.3% vs. 2.9%), while the estimates for the remaining SNPs were comparable between the age groups,” investigators wrote.
The use of a general population cohort with a wide age range was one of the study’s strengths, but several important limitations were noted as well. The population was primarily white, so results may not be generalizable to other ethnicities. PAF is specific to the population it comes from and depends on the prevalence of the risk factor and its risk size.
“These estimates are only valid under the assumption that the risk factor is causal and are also specific for the population from which they were derived,” the researchers wrote.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Evensen L, Arnesen C, Rosendaal F, et al. The risk of venous thromboembolism attributed to established prothrombotic genotypes [published online ahead of print, 2021 Nov 16]. Thromb Haemost. doi: 10.1055/a-1698-6717.