Genetic & Clinical Risk for Human SLE Nephritis

遗传

• 批准号: 6517579
• 负责人: LEE A. HEBERT
• 金额: $ 89.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517579
• 关键词: disease /disorder proneness /risk; genetic susceptibility; human subject; nephritis; pathologic process; patient oriented research; systemic lupus erythematosus

Nephritis is a frequent and severe manifestation of human SLE. Long- term immunosuppression is usually necessary. Relapse is common. SLE nephritis is the result of glomerular accumulation of immune complexes (IC). The risk factors for renal involvement, as well as the determinants of relapse and severity, are poorly understood. We postulate that 1) The dominant mechanism for glomerular IC accumulation is genetic and/or acquired defects of IC clearance proteins. Furthermore, the concurrence of 2 or more defective/deficient IC clearance proteins predisposes to severe nephritis. 2) IC mediate renal inflammation by regulating the local expression of chemotactic cytokines (chemokines). 3) Specific, quantifiable clinical events are triggers for SLE nephritis relapse, and influence disease severity. These hypotheses will be tested by 4 interrelated projects. Projects 1 and 2 analyze genetic polymorphisms of key IC clearance proteins (C2, C4, CR1, FcgammaRIIa, and FcgammaRIIIa), to determine which are susceptibility genes for human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. The genetic testing of Projects 1, 2, and 3 will involve 250 SLE nephritis patients (biopsy proven), 250 SLE patients who have never had nephritis, and 250 matched normals. Patients and siblings of the SLE patients will also be used for transmission disequilibrium testing (TDT). Project 4 is a meticulous, prospective study designed to determine the relationship between SLE relapse and genetic, immunologic, and clinical parameters. One hundred SLE patients with relapsing disease (50 with and 50 without renal manifestations) will be studied longitudinally over 5 years. In collaboration with Projects 1-3, serial quantitative measures of IC clearance proteins, chemokines, and specific clinical factors (stress, sex hormones, infection, UV radiation) will be obtained before, during, and after each of the more than 300 SLE relapses expected during follow-up. These variables will be correlated to disease activity and severity to determine which are "triggers" for SLE relapse, and which are determinants of the renal manifestations of SLE. From this analysis should emerge, for the first time, a clear picture of the risk factors for SLE nephritis and its relapse in humans. Summary: Concepts fundamental to understanding the genetic and clinical risk factors for human SLE nephritis should be revealed, thus providing tools for predicting SLE nephritis relapse and severity, and strategies for its management.

肾炎是人SLE的常见和严重表现。通常需要长期免疫抑制。复发很常见。 SLE肾炎是免疫复合物（IC）的肾小球积累的结果。肾脏参与的风险因素以及复发和严重程度的决定因素知之甚少。我们假设1）肾小球IC积累的主要机制是遗传和/或获得IC清除蛋白的缺陷。此外，有2个或更多缺陷/缺陷的IC清除蛋白的同时发生易于严重的肾炎。 2）通过调节趋化细胞因子（趋化因子）的局部表达来介导肾脏炎症。 3）特定的可量化临床事件是SLE肾炎复发的触发因素，并影响疾病的严重程度。这些假设将由4个相互关联的项目进行检验。项目1和2分析关键IC清除蛋白（C2，C4，CR1，FCGAMMARIIA和FCGAMMARIIIA）的遗传多态性，以确定哪些是人类SLE肾炎的易感基因。项目3研究了调节人SLE肾炎中趋化因子活性的遗传，分子和细胞机制。项目3研究了调节人SLE肾炎中趋化因子活性的遗传，分子和细胞机制。项目1、2和3的基因检测将涉及250名SLE肾炎患者（活检证明），250名从未患有肾炎的SLE患者以及250个匹配的正常患者。 SLE患者的患者和兄弟姐妹也将用于传播不平衡测试（TDT）。项目4是一项细致的前瞻性研究，旨在确定SLE复发与遗传，免疫学和临床参数之间的关系。一百个患有复发性疾病的SLE患者（50例，有50例，没有肾脏表现），将在5年内纵向研究。与项目1-3合作，将在随访期间，随访期间，预期的300多个SLE SLEAPE中的每一个中，将获得IC清除蛋白，趋化因子和特定临床因素（压力，性激素，感染，紫外线辐射）的序列定量测量。这些变量将与疾病的活动和严重程度相关，以确定哪些是SLE复发的“触发器”，哪些是SLE肾脏表现的决定因素。从这种分析中，应该首次出现SLE肾炎的危险因素及其在人类中的复发的清晰图片。摘要：应揭示人类SLE肾炎的遗传和临床危险因素的概念，从而为预测SLE肾炎复发和严重性以及其管理策略提供了工具。