Genetic Polymorphisms in Wegener's Granulomatosis

韦格纳肉芽肿病的遗传多态性

• 批准号: 6328413
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6328413
• 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

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(研究人员摘要)：韦格纳肉芽肿病是 抗中性粒细胞胞浆抗体(ANCA)阳性系统性小血管炎 以炎性病变为特征，伴有肉芽肿形成。 低免疫性肾小球肾炎引起的上呼吸道和下呼吸道 抗蛋白酶3自身抗体(PR#-ANCA)。尽管WG是特发性的，但有 一直对环境因素非常感兴趣，无论是病因还是 加速风险因素。因为流行病学研究表明鼻腔感染 抗葡萄球菌药效的载体和治疗研究 至少对于上呼吸道疾病来说，金黄色葡萄球菌已经吸引了 将大量关注作为这样的环境因素之一。虽然大家一致认为 关于病因仍然难以捉摸，宿主反应的性质已经显现为 疾病表型和严重程度的重要决定因素。有五个月 由环境暴露引发的人类疾病的例子，已经 导致易感性和严重性的重要遗传因素。艾滋病病毒 给出了一个这样的例子。从而识别出重要的遗传因素 对于像WG这样的疾病，不仅是可行的，而且可能是非常有成效的 提供对发病机制和潜在治疗靶点的见解。 依那西普治疗韦格纳肉芽肿病的临床试验 Etanercept Trial，WGET)，我们建议开发一个可再生的遗传库 它将为所有WGET调查人员提供资源，并探索 考生WG素质与遗传多态的关系 分子，因为它们在病理生理学中的作用而被选中。我们还建议 在这些分子中发现新的多态，并将其应用于这一队列。 因此，我们的具体目标是：1)建立可再生的生物 参加WGET临床试验的所有WG患者的资源， 包括每个患者的两个种族和地理匹配的对照； 2)确定已知的基因变异是否与先天的 炎症反应，在淋巴细胞活化和靶抗原生物学中 影响WG的易感性或严重性；3)认识到 关于具有生物学意义的遗传变异的知识库将会增加， 我们将通过直接发现和持续评估来确定 SNP数据库，如果新发现的基因类别变异概述在 特定目标2影响WG的易感性或严重程度。