Polymorphisms of Antiphospholipid Protein Antigens

描述(申请人提供)：抗磷脂综合征(APS)是一种 危及生命的血栓性疾病的特征是 干扰血液凝结的自身抗体。最近的证据表明 凝血蛋白的微小遗传变异可能会影响这种可能性 对于APS患者的血栓形成，无论是通过间接的、附加的风险，还是通过 以影响自身抗体的方式改变靶蛋白的功能 发病率或致病性。此应用程序提供以下建议： 目标1：确定特定候选基因的组合常见变种 与APS合作。1000例APS患者及其父母Will的TDT分析 进行，检查三个具有战略意义的单核苷酸多态 已知与APS病理有关的相互作用的凝血蛋白： 1)抗凝剂，蛋白质S 2.)其血浆抑制物C4b结合蛋白(C4BP) 3.)β2-糖蛋白I，APS的主要抗原，也可能调节蛋白质 S. 目的2：制备功能性重组蛋白S、β2-糖蛋白I和β2-糖蛋白 昆虫细胞系统中的C4BP结构域(野生型和多态)和 比较它们之间的绑定交互作用，以及它们对 S蛋白具有体外功能。 目的3：评价个体黄体生成素血浆中游离蛋白S降低的情况 已知在这些患者中普遍存在，并与其存在相关 或不存在候选多态，且具有该基因的抗体特异性 重组野生型或多态结构域。 单一或组合的遗传因素可能决定三级结构和 APS的几个关键蛋白质靶点之间的相互作用强度 抗体。确定常见多态对发生的影响 和/或自身抗体的致病性可能导致诊断试验的改进 和/或新颖的、基于机制的AP治疗方法。此外，还研究了 这些凝血蛋白之间相互作用的差异是由 常见的、继承的多态将具有内在价值，而不限于 抗磷脂综合征。

DESCRIPTION (provided by applicant): The antiphospholipid syndrome (APS) is a life-threatening thrombotic disorder characterized by a spectrum of autoantibodies that interfere with blood clotting. Recent evidence suggests that minor genetic variations in coagulation proteins may affect the likelihood for thrombosis in APS patients, either by an indirect, additive risk, or by altering the function of target proteins in a way that affects autoantibody incidence or pathogenicity. This application proposes: Aim 1: To determine if combined, common variants of specific candidate genes associate with APS. A TDT analysis of 1,000 APS patients and their parents will be performed, examining strategic single nucleotide polymorphisms in three interacting coagulation proteins known to be implicated in APS pathology: 1.) the anticoagulant, protein S 2.) its plasma inhibitor, C4b Binding Protein (C4BP) 3.) beta 2-glycoprotein I, a major APS antigen which also may regulate protein S. Aim 2: To produce functional, recombinant protein S, beta 2-glycoprotein I and C4BP domains (both wild-type and polymorphic) in an insect cell system and to compare each in binding interactions with the others, and in their effects on protein S function in vitro. Aim 3: To evaluate individual APS plasma for the decreased free protein S which is known to be prevalent in these patients and to correlate this with presence or absence of candidate polymorphisms and with antibody specificities for the recombinant wild type or polymorphic domains. Single or combined genetic factors may determine the tertiary structures and strength of interactions between several, key protein targets of APS antibodies. Determining the impact of common polymorphisms on the occurrence and/or pathogenicity of autoantibodies could lead to improved diagnostic tests and/or novel, mechanism-based treatments for APS. Additionally, the study of differences in interactions between these coagulation proteins conferred by common, inherited polymorphisms will have intrinsic value, not limited to the antiphospholipid syndrome.