Recurrent mutations in a SERPINC1 hotspot associate with venous thrombosis without apparent antithrombin deficiency.
Recurrent mutations in a SERPINC1 hotspot associate with venous thrombosis without apparent antithrombin deficiency.
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SERPINC1 热点的反复突变与静脉血栓形成相关，但没有明显的抗凝血酶缺乏
DOI：
10.18632/oncotarget.21365
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发表时间：
2017-10-13
期刊：
影响因子：
--
通讯作者：
Hu Y
中科院分区：
文献类型：
--
作者：
Zeng W;Hu B;Tang L;You YY;Toderici M;de la Morena-Barrio ME;Corral J;Hu Y
尽管抗凝血酶具有重要的抗凝功能，且与其缺乏相关的血栓形成风险较高，但静脉血栓栓塞症（VTE）患者中抗凝血酶缺乏的患病率非常低。然而，越来越多的证据表明，抗凝血酶缺乏症可能被低估。在1,304名连续的中国VTE患者和1,334名健康对照中，对编码抗凝血酶的基因SERPINC 1的分析显示，涉及残基294和295的热点严重增加了VTE的风险。我们检测到c.883G>A（p.Val295Met）（rs 201381904）突变，11例患者和仅1例对照（OR = 13.6; 95% CI：1.7-107.1）; c.881G>T（p.Arg294Leu）（rs 587776397）;和c.880C>T（p.Arg294Cys）（rs747142328）在两个患者中，但没有对照。此外，在一个对照中鉴定了c.881G>A（p.Arg294His）（rs 587776397）。这些突变在高加索人队列中不存在。这些突变的携带者具有正常的抗凝血酶水平和抗凝活性，与重组模型中获得的结果一致。然而，突变携带者具有显著增加的内源性凝血酶潜力。我们的研究结果表明，中国人群中存在SERPINC 1热点，该热点通过损害止血系统的抗凝能力显着增加了静脉血栓栓塞的风险。当前抗原或体外功能性抗凝血酶试验未显示此效应。
Despite the essential anticoagulant function of antithrombin and the high risk of thrombosis associated with its deficiency, the prevalence of antithrombin deficiency among patients with venous thromboembolism (VTE) is very low. However, increasing evidence suggests that antithrombin deficiency may be underestimated. The analysis of SERPINC1, the gene encoding antithrombin, in 1,304 consecutive Chinese VTE patients and 1,334 healthy controls revealed a hotspot involving residues 294 and 295 that severely increases the risk of VTE. We detected the c.883G>A (p.Val295Met) (rs201381904) mutation in 11 patients and just one control (OR = 13.6; 95% CI: 1.7-107.1); c.881G>T (p.Arg294Leu) (rs587776397) in six patients but no controls; and c.880C>T (p.Arg294Cys) (rs747142328) in two patients but no controls. In addition, c.881G>A (p.Arg294His) (rs587776397) was identified in one control. These mutations were absent in a Caucasian cohort. Carriers of these mutations had normal antithrombin levels and anticoagulant activity, consistent with results obtained in a recombinant model. However, mutation carriers had a significantly increased endogenous thrombin potential. Our results suggest the existence in the Chinese population of a hotspot in SERPINC1 that significantly increases the risk of VTE by impairing the anticoagulant capacity of the hemostatic system. This effect is not revealed by current antigen or in vitro functional antithrombin assays.
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