Analysis of SNPs Associated With WNV-Induced Disease

与西尼罗河病毒引起的疾病相关的 SNP 分析

• 批准号: 6953145
• 负责人: Margo A Brinton
• 金额: $ 24.74万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953145
• 关键词: Flaviviridae; West Nile virus; animal tissue; clinical research; gene frequency; gene mutation; genetic mapping; genetic polymorphism; genetic screening; genetic susceptibility; horses; host organism interaction; human subject; molecular cloning; nucleic acid sequence; polymerase chain reaction; statistics /biometry; virus genetics

Description (provided by applicant): The outcome of a viral infection is the result of a complex interplay between host and viral components. Although the majority of humans show either no clinical symptoms or febrile disease after WNV infection, about 10 to 20% develop severe disease which is sometimes fatal. The elderly are at greater risk for developing disease, but individuals of different ages and without obvious immunodeficiency are represented in the disease population suggesting that a genetic component may be involved in conferring an increased predisposition to disease. Horse populations show a similar response to WNV infection. In mice, a single gene (FIv) alters both the level of flavivirus production and disease outcome. This gene was recently identified by our lab as one of eight 2'-5' oligoadenylate synthetase (Oas)1 genes (Perelygin et al., 2002). Oas genes are part of the innate immune system but the mechanism by which the mouse gene functions is not known. Preliminary data from TBEV-infected humans suggest an association between particular polymorphisms in the OAS gene cluster and disease response. We propose to identify human and horse genes associated with predisposition to severe flavivirus-induced disease using screening of selected polymorphisms in the OAS genes and, if necessary, in other genes in the OAS gene activity pathways in WNV-infected individuals with various responses to infection. Associations between disease susceptibility and particular polymorphisms will be determined statistically. Haplotype blocks will be first identified as a prelude and guide to these analyses. The haplotypes within each block will then be determined, and their frequencies will be compared between the different response groups. Further analyses will include fine mapping and sequencing of the causative mutation(s).

描述（由申请人提供）：病毒感染的结果是宿主和病毒成分之间复杂相互作用的结果。尽管大多数人在感染西尼罗河病毒后没有表现出临床症状或发热性疾病，但约 10% 至 20% 的人会发展为严重疾病，有时甚至致命。老年人患疾病的风险更大，但不同年龄且没有明显免疫缺陷的个体在疾病人群中都有代表性，这表明遗传成分可能与增加患病倾向有关。马群对西尼罗河病毒感染也表现出类似的反应。在小鼠中，单个基因（FIv）可以改变黄病毒的产生水平和疾病结果。该基因最近被我们的实验室鉴定为八个 2'-5' 寡腺苷酸合成酶 (Oas)1 基因之一（Perelygin 等，2002）。 Oas 基因是先天免疫系统的一部分，但小鼠基因发挥作用的机制尚不清楚。来自 TBEV 感染者的初步数据表明，OAS 基因簇中的特定多态性与疾病反应之间存在关联。我们建议通过筛选 OAS 基因中选定的多态性，并在必要时筛选对感染有不同反应的西尼罗河病毒感染者的 OAS 基因活性途径中的其他基因，来鉴定与严重黄病毒引起的疾病易感性相关的人类和马基因。疾病易感性和特定多态性之间的关联将通过统计学确定。首先将确定单倍型块作为这些分析的前奏和指南。然后将确定每个块内的单倍型，并在不同响应组之间比较它们的频率。进一步的分析将包括致病突变的精细定位和测序。