GENETICS OF SEVERE HEPATIC FIBROSIS IN SCHISTOSOMIASIS

严重肝脾疾病合并门脉高压症、食道 精索静脉曲张和出血是感染的最严重后果 曼氏血吸虫。这种情况最具体的指标是 高密度脂蛋白可准确诊断肝纤维化 分辨率超声扫描。虽然感染很普遍，但 这种疾病的患病率在地方性疾病中分布不均 人口数量，并不总是可以通过 感染。许多研究表明，要么是宿主的基因 背景，寄生虫菌株或两者都对 严重疾病的发展。我们假设有一个或几个 主要基因可能与重症心脏病的发生有关。 肝脾血吸虫病。由于现在可以将 在高分辨率的人类基因组中，我们建议量化这种影响 人类遗传因素在重症血吸虫病发生发展中的作用 并确定人类遗传因素对其影响。 重症曼氏血吸虫病的发生发展及基因鉴定 导致这种易感性的基因座。在基于人口的研究中 埃及(高患病率纤维化)和肯尼亚(低患病率 纤维化)，所有受影响的个人将从社区中识别出来 将为曼氏血吸虫高度地方性和家系构建 用复偏聚分析方法对影响因素进行分析，以表征 继承的方式。使用受影响同胞对的DNA，1-10 候选遗传基因座将通过连锁分析确定，使用 用于10点全基因组扫描的多态微卫星标记 厘米分辨率。在第二阶段的筛选中，这10个基因座将被 使用兄弟姐妹及其父母的DNA进行精细定位。至 开始分析寄生虫对疾病的遗传贡献， 此外，还将开发用于曼氏血吸虫的多态标记作为工具 用于分析寄生虫的异质性。这项提议是对以下问题的回应 PA-96-067：寄生虫致病的分子相关性 疾病。

Severe hepatosplenic disease with portal hypertension, esophageal varices and bleeding is the most serious consequence of infection with schistosoma mansoni. The most specific indicator of this condition is hepatic fibrosis that can be accurately diagnosed by use of high resolution ultrasound scanning. While infection is widespread, the prevalence of this form of disease is unevenly distributed in endemic populations and cannot always be predicted by the intensity of infection. Many investigations indicate that either the hosts genetic background, the parasite strain or both contribute significantly to the development of severe disease. We hypothesize that one or a few major genes are likely to be linked to the development of severe hepatosplenic schistosomiasis. Since it is now possible to map the human genome at high resolution, we propose to quantify the influence of human genetic factors on the development of severe schistosomiasis mansoni and to identify the influence of human genetic factors on the development of severe schistosomiasis mansoni and to identify genetic loci that contribute to this susceptibility. In population-based studies in Egypt (high prevalence of fibrosis) and Kenya (low prevalence of fibrosis), all affected individual will be identified from communities highly endemic for S. mansoni and pedigrees will be constructed for affecteds and analyzed by complex segregation analysis to characterize the mode of inheritance. Using DNA from affected sib pairs, 1-10 candidate genetic loci will be identified by linkage analysis using polymorphic microsatellite markers for a complete genome scan at 10 cM resolution. In the second stage of screening, these 10 loci will be fine mapped using DNA from the sib pairs and their parents. To begin an analysis of the parasite genetic contribution to disease, polymorphic markers will also be developed for S. mansoni as tools for analyzing parasite heterogeneity. This proposal is in response to PA-96-067: Molecular Correlates of Pathogenesis in Parasitic Diseases.