Polymorphisms of Antiphospholipid Protein Antigens

描述（由申请人提供）：抗磷脂综合征（APS）是一种 以一系列血栓性疾病为特征的危及生命的血栓性疾病 干扰血液凝固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 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。本申请提出： 目的1：确定特定候选基因的组合常见变体 与APS合作。对1,000名APS患者及其父母的TDT分析将 进行，检查战略单核苷酸多态性在三个 已知与APS病理学有关的相互作用凝血蛋白： 1.）的人。抗凝血剂蛋白S 2.）其血浆抑制剂C4 b结合蛋白（C4 BP） 3.）第三章β 2-糖蛋白I，一种主要的APS抗原，也可调节蛋白质 S. 目的2：制备功能性重组蛋白S，β 2-糖蛋白I， 昆虫细胞系统中的C4 BP结构域（野生型和多态型）以及 比较每一个与其他人的结合相互作用，以及它们对 蛋白S在体外的功能。 目的3：评价个体APS血浆中游离蛋白S的减少， 已知在这些患者中普遍存在，并将其与 或不存在候选多态性，并且具有针对 重组野生型或多态性结构域。 单个或组合的遗传因素可以决定三级结构， APS的几个关键蛋白质靶点之间的相互作用强度 抗体的确定常见多态性对发生的影响 和/或自身抗体的致病性可以导致改进的诊断测试 和/或新的基于机制的APS治疗。此外，研究 这些凝血蛋白之间相互作用的差异， 常见的遗传多态性将具有内在价值，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.