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要么没有临床症状，要么表现出发热性疾病，但大约10%到20%的人会发展成严重的疾病，有时是致命的。老年人罹患疾病的风险更大，但不同年龄和没有明显免疫缺陷的人在疾病人群中有代表，这表明遗传因素可能参与了疾病易感性的增加。马群对西尼罗河病毒感染表现出类似的反应。在小鼠中，单基因(FIV)改变了黄病毒的产生水平和疾病结果。该基因最近被我们实验室鉴定为8个2‘-5’寡腺苷合成酶(OAS)1基因之一(Perelygin等人，2002年)。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与疾病反应之间存在关联。我们建议通过筛选OAS基因中的特定多态来识别与严重黄病毒诱导的疾病易感性相关的人和马基因，如果必要的话，还可以在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中进行筛选。疾病易感性和特定的多态之间的关联将被统计地确定。单倍型区块将首先被确定为这些分析的前奏和指南。然后将确定每个区块内的单倍型，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致病突变的精细图谱和测序(S)。

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).