背景:蛋白C(PC)的R189W和K193del是中国静脉血栓栓塞(VTE)人群的热点突变,但近三分之二的上述突变患者与其他遗传或明显的血栓前危险因素共存。这项研究的目的是阐明R189W或K193del对VTE风险的独立贡献。
方法:本研究纳入了490名具有VTE个人病史的无关患者和410名健康参与者。他们的人口统计数据,家族史,收集遗传和获得性血栓形成危险因素并进行统计学分析。
结果:在3/410(0.7%)和7/410(1.7%)健康对照中发现了PCR189W和K193del,在27/490(5.5%)和43/490(8.8%)的VTE患者中,分别。值得注意的是,这些突变携带者中约有70%与其他遗传或获得性血栓因子结合。调整后的年龄,性别,其他遗传和后天风险因素,我们证明R189W和K193del与VTE风险增加5.781倍和4.365倍相关,分别,显着低于罕见突变引起的抗凝剂缺乏的血栓前风险。独立的R189W或K193del突变与较早的首次发病年龄以及较高的VTE复发率无关。然而,其他遗传或获得性血栓形成因子的组合对这些后果具有超累加效应.患者的额外风险因素越多,较年轻的首次发病年龄和较高的复发风险.
结论:作为中国人群中PC缺乏症最常见的突变,与PROC基因中的其他罕见突变相比,R189W和K193del突变对VTE发展的独立贡献有限,但可能与其他遗传缺陷或获得性血栓形成危险因素协同作用,产生最终的严重表型.
BACKGROUND: R189W and K193del of protein C (PC) were hotspot mutations in Chinese population with venous thromboembolism (VTE), but almost two-thirds of patients with above mutations coexisting with other genetically or aquiredly prothrombotic risk factors. The aim of this
study is to clarify the independent contributions of R189W or K193del to VTE risk.
METHODS: 490 unrelated patients with a personal history of VTE and 410 healthy participants were enrolled in this
study. Data of their demographics, family history, genetic and acquired thrombosis risk factors were collected and statistically analyzed.
RESULTS: PC R189W and K193del were identified in 3/410 (0.7%) and 7/410 (1.7%) healthy controls, and in 27/490 (5.5%) and 43/490 (8.8%) patients with VTE, respectively. Notably, about 70% of these mutant carriers combined with other genetic or acquired thrombophilic factors. After adjustment for age, gender, other inherited and acquired risk factors, we demonstrated that R189W and K193del were associated with 5.781-fold and 4.365-fold increased risk of VTE, respectively, which were significantly lower than the prothrombotic risk of anticoagulant deficiencies induced from rare mutations. Independent R189W or K193del mutation was not associated with earlier first-onset age as well as higher recurrent rate of VTE. However, combination of other genetic or acquired thrombophilic factors had supra-additive effects on those consequences. The more additional risk factors the patients had, the younger first-onset ages and higher risk of recurrence would be.
CONCLUSIONS: As the most frequent mutations for PC deficiency in Chinese population, both R189W and K193del mutations had limited independent contributions to VTE development compared with other rare mutations in PROC gene, but may act in concert with other genetic defects or acquired thrombotic risk factors to produce the final severe phenotype.