Analysis of SNPs Associated With WNV-Induced Disease

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。虽然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，但约有10%至20%的人会出现严重疾病，有时会致命。老年人患病的风险更大，但不同年龄和没有明显免疫缺陷的个体在疾病人群中也有代表，这表明遗传成分可能参与了赋予疾病易感性的增加。马种群对西尼罗河病毒感染表现出类似的反应。在小鼠中，单个基因（FIv）改变黄病毒产生水平和疾病结果。该基因最近被我们的实验室鉴定为8个2‘-5’寡聚腺苷酸合成酶（Oas）1基因之一（Perelygin et al., 2002）。Oas基因是先天免疫系统的一部分，但小鼠基因功能的机制尚不清楚。来自tbev感染者的初步数据表明，OAS基因簇的特定多态性与疾病反应之间存在关联。我们建议在对感染有不同反应的西尼罗河病毒感染个体中，通过筛选OAS基因的选择多态性，并在必要时筛选OAS基因活性途径中的其他基因，来确定与严重黄病毒诱导疾病易感性相关的人和马基因。疾病易感性和特定多态性之间的关联将在统计学上确定。单倍型块将首先被确定为这些分析的前奏和指南。然后确定每个块内的单倍型，并在不同的反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制图和测序。

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).