Host Genetics and Symptomatic Dengue Infection

描述(由申请者提供)：登革热继续在世界范围内传播，并已成为维持和平努力的一个重要因素。然而，它的流行及其与其他重要病毒感染的关系可能使其成为黄病毒和出血热感染的良好模式。感染登革热病毒的一个显著特征是，它能够产生危及生命的疾病，或者仅仅是与根本没有症状的实验室发现有关的疾病。在感染登革热病毒后出现这些极端的疾病表现的一个潜在来源是人类宿主的遗传差异。小鼠的2‘-5’寡腺苷合成酶1b(OAS 1b)基因使它们对所有黄病毒感染具有抵抗力。人类的同源基因--OAS1、2和3基因--与老鼠的基因非常相似。这些基因是串联排列的，它们可能是协同调控的，可能是通过复制而产生的。它们由不同的干扰素诱导，并表现出许多单核苷酸多态和几个大的变种。这项建议描述了一项对巴西萨尔瓦多2002年至2003年严重登革热病例的有限病例对照研究，以期与这三个美洲国家组织基因有关。2002年，该市确诊登革热出血热病例40至60例，典型登革热病例数千例。对人类OAS基因的20个SNP标记的调查将分析等位基因和单倍型频率。等位基因或单倍型与临床表现之间的关联强度将被评估为相对风险，并将对群体亚结构和多重比较进行修正。此外，还将收集人口学和家族学数据，以评估在R01中对严重或典型登革热进行未来家庭关联研究的可能性。除了巴西优秀的流行病学和实验室研究人员外，该项目还依赖于两个小组之间长期的合作历史，凯斯西储大学遗传流行病学部提供的强有力的遗传流行病学支持，以及巴西Evandro Chagas研究所和马里兰州德特特里克堡的合作研究人员提供的血清学实验室支持。这项研究的结果可能有助于预测高危人群，可能影响疫苗设计，或者可能有助于了解和管理其他病毒性出血热。

DESCRIPTION (provided by applicant): Dengue continues to extend its range worldwide and has been a significant factor in peacekeeping efforts. Yet, its prevalence and relationship to other important viral infections may make it a good model of flaviviral and hemorrhagic fever infection. A striking feature of infection with the dengue virus is that it is capable of producing a life-threatening illness or a mere laboratory finding associated with no symptoms at all. A potential source for these extremes in disease presentation following infection with dengue viruses is genetic differences in the human host. The 2'-5' oligoadenylate synthetase 1b (OAS 1b) gene of mice makes them resistant to all flaviviral infections. The human orthologs - the OAS 1, 2 & 3 genes - are very similar to the mouse genes. These genes are arranged in tandem, they may be coordinately regulated and probably arose by duplication. They are differentially induced by a variety of interferons and demonstrate many single nucleotide polymorphisms as well as several large variants. This proposal describes a limited case-control study of severe dengue cases from 2002 and 2003 in Salvador, Brazil for associations with these three OAS genes. There were between 40-60 confirmed cases of dengue hemorrhagic fever and thousands of cases of classic dengue in 2002 in this city. A survey of 20 SNP markers across the human OAS genes will be analyzed for allele and haplotype frequencies. The strength of association between alleles or haplotypes and clinical presentation will be assessed as relative risks and corrections will be made for population substructure and for multiple comparisons. In addition, demographic and familial data will be collected to assess the possibility for future familial linkage studies of severe or classic dengue in an R01. Besides excellent epidemiologic and laboratory investigators in Brazil, the project relies on a long history of collaboration between the groups, strong genetic epidemiology support from the Division of Genetic Epidemiology at Case Western Reserve University and serology laboratory support from co-investigators based at the Evandro Chagas Institute, Brazil and Fort Dettrick, MD. The results of this study may help predict populations at risk, may influence vaccine design or may aid in understanding and managing other viral hemorrhagic fevers.