中国孕产妇静脉血栓栓塞遗传性危险因子作用途径的研究

As one of the major causes of maternal mortality in developed nations, venous thromboembolism (VTE) is dominated to a great extend by individual's genetic risk factors, covering single or multiple genteic mutation. It is assumed that diagnostic limitation led to many VTE women misdiagnosed, and such an inconsistency in incidence was altered in China during the recent year due to improved diagnostic methods and concepts. But still have Chinese obstetrical clinicians not fully been aware of the importance in preventing and treating maternal VTE, many of them still believe obstetrical hemorrhage as the mere prominent cause to maternal mortality. One of the major reasons for this phenomenone is missing of maternal VTE incidence in Chinese population. Literature searching indicated that no relevant perspective cohort study with a large sample size is available in China. Meanwhile the mechanism and expression of genetic risk factors in Chinese maternal VTE also remains yet to be investigated. This proposed study is planned to collaborate with 11 hospitals in Shanghai to enroll 5,5000 women at first-trimester gestional age within approximate one year. All of them will be followed up to 42 days after their child birth. Among them, any VTE suspection will be confirmed by pre-established diagnosis criteria. Through which, the incidence of maternal VTE in Chinese population can be obtained. All idenfitied VTE cases will be invited to participate in a nested case-control study, which is aimed to investigate the mutation rate of genetic risk factors to maternal VTE, and the interaction of genetic and acquired risk factors to maternal VTE. This study will be the first maternal VTE perspective cohort study in China. Based on solid data of this study, a maternal VTE prediction mathematical model will be established, which is set to provide theoretical support for prevention and treatment of maternal VTE in Chinese population.

静脉血栓栓塞(VTE)是发达国家孕产妇主要死亡原因之一，遗传性危险因子在其发生过程中扮演了重要角色，涉及单一或多个相关基因的缺陷或突变。随着诊断水平的提高，近年来VTE在我国孕产妇死亡原因构成明显增加。但国内临床医师仍未充分认识到防治孕产妇VTE的重要性，我国孕产妇VTE发病率至今空白，同时未见设计严谨的孕产妇VTE遗传性危险因子作用途径的研究。本项目将与上海市11家医院合作，用1年左右的时间招募5.5万早孕妇女，密切观察至其产后42天，发现所有VTE患者，以获得我国孕产妇VTE发病率资料。同时，以新发VTE患者为病例开展巢式病例对照研究，利用分子生物学技术，探讨孕产妇VTE遗传性危险因子的作用途径，分析关键遗传性危险因子在我国孕产妇VTE患者中基因缺陷或突变发生率、分析获得性危险因子与遗传性危险因子的交互作用，建立孕产妇VTE 风险预测数学模型，以为我国孕产妇VTE防治提供依据。

静脉血栓栓塞(VTE)是发达国家孕产妇主要死亡原因之一，遗传性危险因子在其发生过程中扮演了重要角色。目前尚无我国孕产妇发生率数据，且VTE的病因尚未得到充分了解。本研究通过开展孕妇队列建立和随访和巢式病例对照研究，获得我国孕产妇VTE发病率资料，探讨孕产妇VTE遗传性危险因子的作用途径，分析关键遗传性危险因子在我国孕产妇VTE患者中基因缺陷或突变发生率、建立孕产妇VTE 风险预测数学模型，为我国孕产妇VTE防治提供依据。..孕妇队列：本研究建立了多家综合医院和妇产科医院首次建立孕期保健卡的65138名孕妇组成队列并随访至产后42天。结果共发现深静脉血栓（VTE）患者27例，VTE粗发病率为54.05/10万妇女(95%CI为36.85~79.10/10万妇女)。进一步分析发现，孕产妇年龄每增加一岁，VTE发生风险增加21%（RR1.21，95%CI1.12-1.31），经用上海市孕产妇年龄构成进行标化，结果,VTE年龄标化发病率（SIR）为62.59/10万妇女（95% CI 57.07%~90.76%）。其中，占总人群仅7.41%的35岁以上高龄生育人群VTE罹患风险最高，其人群归因危险度（PAR）为10.82/10万妇女，人群归因危险度百分比（PAR%）为20.01%。..巢式病例对照研究：以观察队列中的新发现的VTE对象为病例组，正常孕妇为对照组，开展配对巢式病例对照研究，结果显示高脂食物孕前摄入量、孕前每周无氧运动、近期远途出差与VTE的发生相关联。全外显子测序扫描筛查出的7个突变位点与VTE的发生有显著关联。其中rs12401573（2.55，95%CI为1.16 – 5.61）、rs4140974（2.60，95%CI为1.15 – 5.85）、rs199973381（2.60，95%CI为1.15 – 5.85）、rs2055979（2.71，95%CI为1.12 – 6.60）为VTE的风险因素；rs187692176（0.22，95%CI为0.05 – 0.92）、rs7130943（0.31，95%CI为0.11 – 0.84）、和rs140717803（0.25，95%CI为0.07 – 0.82）为VTE的保护性因素。