GENETICS OF SEVERE HEPATIC FIBROSIS IN SCHISTOSOMIASIS

重度肝脾疾病伴门脉高压症，食管 静脉曲张和出血是感染的最严重后果， 曼氏鱼 这种情况最具体的指标是 高灵敏度超声心动图诊断肝纤维化 分辨率超声扫描。 虽然感染是广泛的， 这种疾病的流行在地方病中分布不均匀， 人口，并不能总是预测的强度 感染 许多研究表明，无论是宿主的遗传 背景，寄生虫菌株或两者都显著地有助于 严重疾病的发展。 我们假设一个或几个 主要基因可能与严重的 肝脾血吸虫病 由于现在可以绘制 在高分辨率的人类基因组，我们建议量化的影响， 人类遗传因素对重症血吸虫病发病的影响 mansoni和确定人类遗传因素对 重症曼氏血吸虫病的发生及遗传学鉴定 这些基因座导致了这种易感性。 基于人群的研究 在埃及（纤维化发病率高）和肯尼亚（纤维化发病率低）， 纤维化），所有受影响的个体将从社区中确定 高度流行于S. mansoni和谱系将被构建为 通过复杂的偏析分析来表征 继承的方式。 使用来自受影响同胞对的DNA，1-10 候选遗传基因座将通过连锁分析确定， 多态性微卫星标记的全基因组扫描在10 cM分辨率。 在筛选的第二阶段，这10个位点将被 用同胞和父母的DNA绘制的精细图谱 到 开始分析寄生虫对疾病的遗传贡献， 还将为S.开发多态性标记。mansoni作为工具 用于分析寄生虫异质性。 这项建议是为了回应 PA-96-067：寄生虫发病机制的分子相关性 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.