New research headed by a team at Lund University, Sweden, has identified three common gene variants that significantly raise the risk of venous thrombosis, a discovery the researchers contend is the most important genetic finding relating to blood clots since the discovery of Factor V Leiden. The study, published in the journal Research and Practice in Thrombosis and Haemostasis, showed that variants in the ABO, F8, and VWF genes can raise the risk of blood clots in the leg by up to 180%, and the team developed a risk scoring system based on this discovery. These variants were previously linked to plasma levels of coagulation factor VIII (FVIII) and von Willebrand factor (VWF), both of which are known to influence the risk of venous thromboembolism (VTE).
The implications for clinical care are considerable. The researchers propose that the 3-variant risk score could be used to guide treatment decisions, particularly the duration of anticoagulant therapy after a clotting event. “I think tailoring treatment based on risk assessment will become increasingly important,” said senior author Bengt Zöller, MD, a specialist in general medicine at Skåne University Hospital and professor of general medicine at Lund University.
The impetus for the research stemmed from prior genome wide association studies (GWAS) linking various loci, including ABO, F8, and VWF, to plasma FVIII and VWF levels, though impact of these variants has remained unclear. To further examine the effects of these variants, researchers used exon sequencing to look for both common and rare variants in these genes among 28,794 individuals sourced from the Malmö Diet and Cancer Study without a prior VTE diagnosis. Participants were followed from 1991 through 2018.
Each variant individually increased the risk of VTE by 10% to 30%. A cumulative risk score based on these three variants showed that individuals carrying five risk alleles had a 2.8-fold increased risk of venous thromboembolism.
“We found 3 independent ABO, F8, and VWF variants that are all likely functional to be significantly associated with VTE and created a risk score linked to incident VTE risk in a dose-dependent way,” the researchers wrote.
To develop their risk scoring system, the researcher took a two-step approach. First, they eliminated 27 rare variants (present in less than 0.1% of the population). After testing, none of these gene variants were found to be significant, confirming prior research that showed they are not strongly associated with VTE. They then moved on to the three common variants that were independently and significantly associated with VTE: rs8176719 in ABO (a frameshift mutation determining blood group O), rs1800291 in F8 (a missense mutation: p.Asp1260Glu), and rs1063856 in VWF (a missense mutation: p.Thr789Ala).
Each variant showed a modest but varying increase in VTE risk. Using this information, the team created a cumulative risk score by assigning one point per risk allele carried. People could have between zero and five risk alleles (e.g., someone homozygous for one variant and heterozygous for another would score three).
The study adds to prior research linking Factor V Leiden and other rare mutations to thrombosis risk. But unlike Factor V Leiden, which is only found in people of European ancestry, these newly identified variants are found in between 5% and 50% of various populations around the world, making them potentially more relevant for risk prediction among broad populations.
The team found that the genetic risk score’s performance was similar to or better than classical thrombophilias such as Factor V Leiden and prothrombin mutations, particularly in older individuals. However, they noted that familial risk for VTE tends to decline with age, and genetic risk may be more predictive in younger populations.
The 3-variant score is a potentially valuable tool for identifying VTE risk across ethnic groups and age ranges, particularly when incorporated into personalized risk assessments or treatment planning. Next steps include validating the findings in more diverse cohorts and determining whether the genetic score can enhance current thrombophilia testing or can stratify risk in clinical settings.
