Thrombotic risk determined by ABO, F8, and VWF variants in a population-based cohort study

Background Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) plasma levels are associated with increased risk for venous thromboembolism (VTE). Objectives This study aimed to determine the thrombotic risk of rare and common variants of 27 genes linked to VWF or FVIII plasma levels in genome-wide association studies. Methods Exon sequences of 27 genes linked to plasma levels of VWF or FVIII in genome-wide association studies were analyzed for common and rare variants in 28,794 subjects without VTE (born during 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996), with a follow-up time until 2018. Hazard ratios (HRs) were determined. P values were Bonferroni-corrected ( P value=.05/27 <.0019). Common variants were analyzed individually. Rare qualifying variants (<0.1%) were collapsed. Results None of the 27 genes were associated with VTE in the rare variant collapsing analysis. Three common exon variants were significantly associated with VTE: rs8176719 (frameshift) in ABO (HR = 1.30; 95% CI, 1.20-1.42; P = 3.9 × 10 −10 ), rs1800291 (p.Asp1260Glu) in F8 (HR = 1.29; 95% CI, 1.08-1.55; P = .00046 for men; HR=1.17; 95% CI, 1.06-1.29; P = .00019 for women), and rs1063856 (p.Thr789Ala) in VWF (HR = 1.10; 95% CI, 1.04-1.17; P = .00057). A risk score of these 3 variants was dose-dependently associated with VTE (5 risk alleles): HR=2.8; 95% CI, 1.7-4.7; and P value=.00008. The area under the curve for VTE in receiver operating characteristics for the risk score was similar to FV Leiden (0.55 vs 0.54). Conclusion The risk score of 3 common variants in VWF , F8 , and AB0 genes is associated with VTE risk similar to FV Leiden.