抗β2GPI抗体产生的遗传易感性及其诱导血栓形成的分子机制研究

Anti-β2GPI antibody is the most prominent type in antiphospholipid antibodies and a common risk factor for thrombotic diseases such as ischemic stroke and venous thrombosis. Previous research indicated that aβ2GPI is estimated to be present in 7.5% patients diagnosed with venous thrombosis in White populations. However, its prevalence in the Chinese population remains unknown. For many years, how auto-antibodies against β2glycoprotein I develop and the reason why they are pro-thrombotic is unclear. Recently, we identified 4 novel polymorphisms in the gene encoding β2GPI, which were shown to be associated with an increased risk of thrombosis in the Chinese population. We hypothesized that these SNPs may also be the causes of the conformational change in β2GPI and the formation of aβ2GPI. In this proposal, we intend to explore the prevalence of the aβ2GPI, the association between aβ2GPI and β2GPI gene haplotype, and the relative risk of the haplotype for thrombosis by using a case-control study involving a large number of participants. In addition, we intend to investigate the molecular mechanisms of the intracellular signaling pathways in the development thrombosis induced by aβ2GPI. Individuals at high-risk for thrombosis will benefit from early diagnosis and prevention. In addition, the molecular basis of thrombosis caused by aβ2GPI will provide new methods for anti-thrombotic targeting therapy.

以血浆β2糖蛋白Ⅰ（β2GPI）为靶抗原的抗体aβ2GPI是抗磷脂抗体的最重要类型，也是脑血栓、静脉血栓形成等血栓性疾病的独立危险因素。已有研究表明在白种人群静脉血栓患者中aβ2GPI存在的比例约为7.5%，而其在中国人群中存在的比例未知。此外，aβ2GPI产生的原因、其产生是否具有遗传易感性及其在体内引起血栓形成的机制也不明确。研究中我们在β2GPI的编码基因发现4种新的基因多态性是我国人群静脉血栓形成的遗传危险因素，这些基因变异可能与β2GPI蛋白构象改变以及aβ2GPI的产生有关。本项目拟通过大样本的病例-对照研究明确基因多态性和aβ2GPI产生的相关性以及二者对血栓性疾病的相对危险度；通过基因敲除动物模型、转录组芯片和比较蛋白质组技术等方法探索aβ2GPI引起血栓形成的细胞内信号通路。研究成果可使高危人群获益于早期诊断和预防，并为抗栓的靶向治疗提供新依据。

以β2糖蛋白Ⅰ为靶抗原的抗β2GPI抗体（aβ2GPI）是抗磷脂抗体的最重要类型，也是脑血栓、静脉血栓形成等血栓性疾病的独立危险因素。以狼疮抗凝物为参考，估计我国静脉血栓患者中aβ2GPI存在的比例约为5%-8%。然而aβ2GPI产生的原因及其产生是否具有遗传易感性尚不明确。本项目研究中我们发现4种新的APOH基因多态性是我国人群静脉血栓形成的遗传危险因素，其单倍型与β2GPI蛋白构象改变以及aβ2GPI的产生有关。大样本的研究明确杂合单倍型H2个体患VT的风险是野生单倍型H1的1.29倍，纯合单倍型H3OR可达6.04倍，即H3型个体患静脉血栓的风险提高6倍之多。APOH多态性的筛查可使高危人群获益于早期诊断和预防。