Genetic Polymorphisms in Wegener's Granulomatosis

韦格纳肉芽肿病的遗传多态性

• 批准号: 6658217
• 负责人: JEFFREY C EDBERG
• 金额: $ 30.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6658217
• 关键词: Wegener's granulomatosis; clinical research; cooperative study; gene environment interaction; genetic polymorphism; genetic registry /resource /referral center; genetic susceptibility; human genetic material tag; human subject; inflammation; single nucleotide polymorphism

DESCRIPTION (investigator's abstract): Wegener's Granulomatosis is one of the anti-neutrophil cytoplasmic antibody (ANCA) positive systemic vasculitides which is characterized by inflammatory lesions with granuloma formation in the upper and lower airways, by pauci-immune glomerulonephritis and by anti-proteinase 3 autoantibodies (PR#-ANCA). Although WG is idiopathic, there has been substantial interest in environmental factors as either etiologic or accelerating risk factors. Because of epidemiological studies implicating nasal carriage and therapeutic studies implicating efficacy of anti-staphylococcal agents at least for upper airway disease, Staphylococcus aureus has attracted substantial attention as one such environmental factor. Although consensus about etiology remains elusive, the nature of the host response has emerged as an important determinant for disease phenotype and severity. There are may examples of human disease, provoked by environmental exposures, which have important genetic factors contributing to both susceptibility and severity. HIV presents one such example. Thus the identification of important genetic factors in a disease such as WG is not only feasible but also potentially very fruitful in providing insights into pathogenesis and potential therapeutic targets. Building on the clinical trial of Etanercept in WG (Wegener's Granulomatosis Etanercept Trial, WGET), we propose to develop a renewable genetic repository which will provide resources to all WGET investigators and to explore the relationship between the WG diathesis and genetic polymorphisms in candidate molecules, selected for their role in pathophysiology. We also propose to discover new polymorphisms in such molecules and apply these to this cohort. Accordingly, our specific aims are: 1) To establish a renewable biological resource of all WG patients screened and enrolled in the WGET clinical trial, including two ethnically and geographically matched controls for each patient; 2) To determine if known variations in genes involved in the innate inflammatory response, in lymphocyte activation and in target antigen biology influence the susceptibility to or severity of WG; 3) Recognizing that the knowledge base about biologically significant genetic variants will increase, we will determine, through direct discovery and through continual evaluation of SNP databases, if newly identified variation in gene categories outline in Specific Aim 2 influence the susceptibility to or severity of WG.

描述（研究者摘要）：韦格纳肉芽肿病是一种 抗中性粒细胞胞浆抗体（ANCA）阳性系统性血管炎 其特征在于在组织中形成肉芽肿的炎性病变， 上和下呼吸道，通过少免疫性肾小球肾炎和 抗蛋白酶3自身抗体（PR#-ANCA）。虽然WG是特发性的， 一直对环境因素作为病因或 加速风险因素。因为流行病学研究表明鼻 涉及抗葡萄球菌效力的携带和治疗研究 至少对于上呼吸道疾病，金黄色葡萄球菌已经吸引了 作为一个环境因素的重要性。虽然共识 关于病因仍然难以捉摸，宿主反应的性质已经出现， 疾病表型和严重程度的重要决定因素。有五月 由环境暴露引起的人类疾病的例子， 导致易感性和严重程度的重要遗传因素。艾滋病毒 提供了一个这样的例子。因此重要遗传因素的鉴定 不仅可行，而且可能非常富有成效 在提供发病机制和潜在的治疗靶点的见解。 依托依那西普治疗韦格纳肉芽肿病的临床试验 依那西普试验，WGET），我们建议开发一个可再生的基因库 这将为所有WGET调查人员提供资源，并探索 应征者WG素质与遗传多态性的关系 分子，选择它们在病理生理学中的作用。我们亦建议 在这些分子中发现新的多态性，并将其应用于这一群体。 因此，我们的具体目标是：1）建立可再生的生物 筛选并参加WGET临床试验的所有WG患者的资源， 每例患者包括两个种族和地理位置匹配的对照组; 2)为了确定是否已知的基因变异涉及先天性 炎症反应、淋巴细胞活化和靶抗原生物学 影响WG的易感性或严重性; 3）认识到 关于具有生物学意义遗传变异的知识基础将会增加， 我们将通过直接发现和持续评估， SNP数据库，如果新发现的基因类别中的变异概述在 具体目标2影响WG的易感性或严重性。