Host Genetics and Symptomatic Dengue Infection

描述（由申请人提供）：登革热继续在世界范围内扩大其范围，并一直是维持和平努力的一个重要因素。然而，它的流行和其他重要的病毒感染的关系，可能使它成为一个很好的模型黄病毒和出血热感染。登革热病毒感染的一个显著特征是，它能够产生危及生命的疾病，或者仅仅是实验室发现而没有任何症状。感染登革病毒后出现这些极端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'寡腺苷酸合成酶1b（OAS 1b）基因使它们对所有黄病毒感染具有抵抗力。人类直系同源物-OAS 1、2和3基因-与小鼠基因非常相似。这些基因串联排列，可能是协同调控的，可能是通过复制产生的。它们由多种干扰素差异诱导，并表现出许多单核苷酸多态性以及几个大的变体。该建议描述了一项有限的病例对照研究，从2002年和2003年在巴西萨尔瓦多的严重登革热病例与这三个OAS基因的关联。2002年，该市有40-60例确诊的登革出血热病例和数千例典型登革病例。将对人类OAS基因中的20个SNP标记的调查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校正。此外，还将收集人口统计学和家族数据，以评估未来在R 01中进行严重或经典登革热家族连锁研究的可能性。除了巴西优秀的流行病学和实验室研究人员外，该项目还依赖于各小组之间长期的合作历史，凯斯西储大学遗传流行病学部门的强大遗传流行病学支持以及巴西Evandro Chagas研究所和马里兰州Fort Dettrick的共同研究人员的血清学实验室支持。这项研究的结果可能有助于预测风险人群，可能影响疫苗设计或可能有助于理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.