HOST GENETICS AND SYMPTOMATIC DENGUE INFECTION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项建议将利用巴西城市萨尔瓦多的一项病例对照研究，调查人类对登革热，或许还有其他病毒的反应发生变化的遗传基础。黄病毒，登革病毒，有四种血清型，通过蚊子在血餐中有效地传播给人类。大多数原发登革热感染都是有症状的，很少与登革出血热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带有新的登革热血清型的继发感染之后，主要是通过抗体介导的免疫增强。然而，这一假说不能充分解释严重登革热感染在许多人类中的时段性分布，也不能充分解释初次感染后偶尔出现的DHF。一些证据表明，宿主遗传也可能导致易感性，某些非洲人口似乎对严重的登革出血热感染具有高度抵抗力就是明证。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号染色体区域的常见多态，并在病例和对照中对该区域进行基因分型，然后寻找与临床表现的关联。病例和对照将在年龄、性别以及原发或继发感染方面匹配。分析将使用McNemar检验和Logistic回归，并通过基因组控制方法校正种群结构。

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.