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: 6912093
• 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/6912093
• 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。尽管大多数人类在WNV感染后没有表现出没有临床症状或发热疾病，但大约10％至20％的人会出现严重疾病，有时是致命的。老年人面临着疾病的风险更大，但是不同年龄且没有明显的免疫缺陷的个体在疾病人群中表示，这表明遗传成分可能涉及增加对疾病的倾向。马种群显示出与WNV感染相似的反应。在小鼠中，单个基因（FIV）都会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'寡核苷酸合成酶（OAS）1基因之一（Perelygin等，2002）。 OAS基因是先天免疫系统的一部分，但尚不清楚小鼠基因功能的机制。来自TBEV感染的人的初步数据表明，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，在WNV感染的个体中具有各种感染反应的人的OAS基因活性途径中的其他基因中，使用筛选OAS基因中选定的多态性以及在OAS基因中的其他基因中筛选对严重的黄病毒诱导的疾病的易感性。疾病易感性与特定多态性之间的关联将在统计上确定。单倍型块将首先被识别为这些分析的前奏和指南。然后将确定每个块中的单倍型，并将其频率在不同响应组之间进行比较。进一步的分析将包括对因果突变的精细映射和测序。