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

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2025-05-01 DOI:10.1016/j.rpth.2025.102875

Eric Manderstedt , Christer Halldén , Christina Lind-Halldén , Johan Elf , Peter J. Svensson , Gunnar Engström , Olle Melander , Aris Baras , Luca A. Lotta , Bengt Zöller

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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.

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在一项基于人群的队列研究中，由ABO、F8和VWF变异决定的血栓形成风险

血友病因子（VWF）和凝血因子VIII （FVIII）血浆水平与静脉血栓栓塞（VTE）风险增加相关。目的本研究旨在确定全基因组关联研究中与VWF或FVIII血浆水平相关的27个基因的罕见和常见变异的血栓形成风险。方法对参加Malmö饮食与癌症研究（1991-1996）的28,794名无VTE受试者（1923-1950年出生，60%为女性）的27个与VWF或FVIII血浆水平相关的基因的sexon序列进行分析，随访至2018年。测定风险比（hr）。P值经bonferroni校正（P值= 0.05 /27 < 0.0019）。对常见变异进行单独分析。罕见的合格变异（<0.1%）被摧毁。结果27个基因中没有一个与VTE相关。三个常见的外显子变异与VTE显著相关：ABO中的rs8176719（移码）(HR = 1.30；95% ci, 1.20-1.42；P = 3.9 × 10−10)，F8中rs1800291 (P . asp1260glu) (HR = 1.29；95% ci, 1.08-1.55；男性P = .00046；Hr = 1.17；95% ci, 1.06-1.29；女性P = 0.00019)和VWF的rs1063856 (P . thr789ala) (HR = 1.10；95% ci, 1.04-1.17；P = .00057)。这3种变异的风险评分与VTE呈剂量依赖性相关（5个风险等位基因）：HR = 2.8；95% ci, 1.7-4.7；P值= 0.00008。VTE在受试者操作特征中的曲线下面积与FV Leiden相似（0.55 vs 0.54）。结论VWF、F8和AB0基因3个常见变异的风险评分与VTE风险的相关性与FV Leiden相似。

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