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

Abstract

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.

Keywords: ABO blood-group system; factor VIII; molecular epidemiology; venous thromboembolism; von Willebrand factor.

Figure 1

Kaplan–Meier curves for the 3 lead variants associated with VTE risk: (A) rs8176719 in ABO, (B) rs1800291 in F8 (for females), and (C) rs1063856 in VWF. VTE, venous thromboembolism; VWF, von Willebrand factor.

Figure 2

Kaplan–Meier curves for the number of risk alleles in the 3-variant risk score (rs8176719, rs1800291, and rs1063856). The following model is used: risk is increased for one or more of the insertion rs8176719 in ABO, for every major allele of rs1800291 in F8 (hemizygote men are modeled as carrying 2 risk alleles in F8), or for each minor allele of rs1063856 in VWF. A broken y-axis is inlaid for clarity. VTE, venous thromboembolism; VWF, von Willebrand factor.