The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels
The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels
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DOI：
10.1160/th04-09-0629
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发表时间：
2005-03-01
影响因子：
6.7
通讯作者：
Bernardi, F
中科院分区：
文献类型：
--
作者：
Scanavini, D;Legnani, G;Bernardi, F
第VIII因子(FVIII)水平升高是公认的静脉血栓形成的危险因素。最近的家系研究表明，395IC/G(D1241E)FVIII基因的G等位基因与FVIII活性降低有关。我们在病例对照研究中调查了D1241E基因改变的生物学效应(FVIII水平和活化蛋白C敏感性比率)和临床相关性(静脉血栓栓塞症)。在145名健康女性和150名血栓患者中，1241E等位基因与FVIII水平降低11%相关(t检验，P<；0.05)。对活化蛋白C敏感率的影响无统计学意义。在22.8%的对照组和15.3%的病例中发现了1241E等位基因的携带者，该等位基因具有潜在的血栓保护作用。在另一组F V Leiden携带者(n=283)中，1241E等位基因携带率在143例无症状受试者中为25.2%，在140例血栓患者中为17.1%。我们的数据没有表明与因子V莱顿存在特定的相互作用。这些基因分布表明，1241E FVIII对静脉血栓有轻微的保护作用，但被其他遗传和/或环境成分掩盖，只有在非常大的人群研究中才能检测到。我们的发现表明，凝血因子水平的遗传决定因素在生物学上具有重要作用，但在评估已确定的危险因素之外的血栓风险方面的预测价值较差。
Elevated factor VIII (FVIII) levels are a recognized risk factor for venous thrombosis. Recently, family studies suggested that the G allele of the 395IC/G (D1241E) FVIII polymorphism is associated to lower FVIII activity. We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change. Among 145 healthy and 150 thrombotic women, not carriers of known thrombophilic defects, the 1241E allele was associated with 11% reduced (t-test, P < 0.05) FVIII levels. The effect on activated protein C sensitivity ratio was not statistically significant. Carriership of the 124 1 E allele, potentially conferring protection from thrombosis, was found in 22.8% of controls and in 15.3% of cases. In an additional cohort of factor V Leiden carriers (n=283), carriership of the 1241E allele was 25.2% among 143 asymptomatic subjects and 17.1% among 140 thrombotic patients. Our data do not indicate a specific interaction with factor V Leiden. These genotype distributions suggest a mild protective effect from venous thrombosis conferred by 1241E FVIII, masked by other genetic and/or environmental components, and detectable only in very large population studies. Our findings point toward the presence of genetic determinant of coagulation factor levels with a biologically significant role, but with a poor predictive value to estimate thrombotic risk beyond established risk factors.