HOST GENETICS AND SYMPTOMATIC DENGUE INFECTION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。这项提案将利用巴西萨尔瓦多市的病例对照研究，调查人类对登革热以及其他病毒反应变异的遗传基础。黄病毒，登革热病毒，有四种血清型，并在吸血期间通过蚊子有效地传播给人类。大多数原发性登革热感染是有症状的，很少与登革出血热（DHF）和登革休克综合征有关。相反，严重的登革热并发症最常发生在继发感染新的登革热血清型后，主要是通过抗体介导的免疫增强。然而，这一假设并不能充分解释严重登革热感染在许多人中的偶发性分布，也不能解释原发感染后偶尔发生的DHF。一些证据表明，宿主遗传学也可能导致易感性，某些非洲人群对严重的DHF感染具有高度抵抗力。这些计划包括收集、分离和验证具有不同临床表现的病例和对照的DNA，选择12号染色体区域中的常见多态性，并对病例和对照中的该区域进行基因分型，然后寻找与临床表现的关联。病例和对照组将在年龄、性别和原发性或继发性感染方面相匹配。将使用McNemar检验和逻辑回归进行分析，并通过基因组对照方法校正群体结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal will investigate the genetic basis for variation in human responses to dengue, and perhaps other viruses, using a case-control study in the Brazilian city of Salvador. The flavivirus, Dengue virus, has four serotypes and is efficiently transmitted to humans by mosquitoes during a blood meal. Most primary dengue infections are symptomatic and only rarely associated with dengue hemorrhagic fever (DHF) and dengue shock syndrome. Rather, severe dengue complications occur most frequently following a secondary infection with a new dengue serotype, primarily by antibody mediated immune enhancement. This hypothesis, however, does not adequately explain the episodic distribution of severe dengue infection in many humans, nor the occasional DHF following primary infection. Several lines of evidence suggest that host genetics may also contribute to susceptibility, as evidenced by certain African populations who appear highly resistant to severe DHF infections. The plans include collection, isolation, and validation of DNA for cases and controls with differing clinical presentations, selecting common polymorphisms in a region of Chromosome-12, and genotyping that region in cases and controls, then looking for associations with the clinical presentations. Cases and controls will be matched for age, sex and for primary or secondary infection. Analysi\es will be performed using McNemar's test and logistic regression with correction for population structure via a genomic control approach.