Zeng Wei, Hu Bei, Tang Liang, You Yan-Yan, Toderici Mara, de la Morena-Barrio Maria Eugenia, Corral Javier, Hu Yu
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Oncotarget. 2017 Sep 28;8(48):84417-84425. doi: 10.18632/oncotarget.21365. eCollection 2017 Oct 13.
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 , 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 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 functional antithrombin assays.
尽管抗凝血酶具有重要的抗凝功能，且其缺乏与血栓形成的高风险相关，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，抗凝血酶缺乏可能被低估了。对1304例连续的中国VTE患者和1334例健康对照者中编码抗凝血酶的基因进行分析，发现了一个涉及294和295位氨基酸残基的热点区域，该区域会严重增加VTE风险。我们在11例患者中检测到c.883G>A（p.Val295Met）（rs201381904）突变，而在仅1例对照者中检测到该突变（比值比=13.6；95%置信区间：1.7 - 107.1）；在6例患者中检测到c.881G>T（p.Arg294Leu）（rs587776397）突变，对照者中未检测到；在2例患者中检测到c.880C>T（p.Arg294Cys）（rs747142328）突变，对照者中未检测到。此外，在1例对照者中鉴定出c.881G>A（p.Arg294His）（rs587776397）突变。这些突变在白种人队列中不存在。这些突变携带者的抗凝血酶水平和抗凝活性正常，这与重组模型中获得的结果一致。然而，突变携带者的内源性凝血酶潜力显著增加。我们的结果表明，中国人群中存在一个基因热点区域，该区域通过损害止血系统的抗凝能力显著增加VTE风险。目前的抗原或抗凝血酶功能检测未发现这种效应。
