HOST GENETIC CORRELATES IN SCHISTOSOMIASIS

该ICIDR是纽约州立大学和巴西菲奥克鲁斯研究所合作开展的一项遗传流行病学研究，以确定在控制血吸虫感染和疾病发展中至关重要的宿主遗传因素。识别调节血吸虫宿主-寄生虫相互作用的宿主基因将为理解人类的免疫机制提供新的途径，而免疫机制对于确定对再感染的敏感性/抵抗力和疾病的发展至关重要。我们的研究将在流行区的受试者身上进行，他们在自然传播条件下接触到这种寄生虫，在那里遗传、免疫和环境因素之间会发生复杂的相互作用。为了实现我们的目标，我们将对居住在不同地区的曼氏血吸虫病流行地区的扩展家系进行纵向研究，研究对确定的和粗制的抗原的免疫反应。这一分析的结果将为我们提供一组免疫标记(表型)来确定曼氏沙门氏菌抗原，然后进行定量遗传分析。由于定量遗传分析的目的是确定基因和环境对特定性状变异的相对贡献，我们将确定环境因素对观察到的表型的贡献，因为它们与再次感染的易感性/抵抗力和疾病状态有关。然后，我们将使用最大似然方差分量方法测试与再次感染的易感性/抵抗力和临床结果相关的免疫表型变异来源的假设。方差分量方法将允许我们将性状的方差在遗传因素、系统环境因素(例如，水接触)和随机环境因素(未知因素)的分量之间进行划分。最后，我们将进行连锁分析和联合连锁/不平衡分析，以确定与再次感染易感性/抵抗力和疾病结局相关的免疫表型表达所涉及的候选基因的贡献。拟议的项目是第一步，以证明宿主遗传因素确实参与了血吸虫与人类的相互作用。我们的遗传流行病学研究的最终目标是识别和定位影响血吸虫病感染和疾病的特定基因。我们希望提高我们对血吸虫病再感染抵抗力和疾病进展的潜在遗传决定因素的理解。

This ICIDR is a collaboration between the State University of New York and the FIOCRUZ (Brazil) to perform a genetic epidemiological study to determine host genetic factors critical in controlling schistosome infection and disease development. The identification of host genes regulating schistosome host- parasite interactions will provide new ways to understand the immune mechanisms in humans that are critical for determining susceptibility/resistance to reinfection and disease development. Our studies will be performed on subjects from endemic areas, who are exposed to the parasite under natural conditions of transmission, where complex interactions between genetic, immunological and environmental factors occur. To accomplish our goals we will study the immune response to defined and crude antigens in a longitudinal study of extended pedigrees residing in different areas endemic for schistosomiasis mansoni. The results of this analysis will provide us with a panel of immune markers (phenotypes) to defined S. mansoni antigens which will then undergo quantitative genetic analysis. As the aim of quantitative genetic analysis is to determine the relative contributions of genes and environment to the variation of a given trait, we will determine the contribution of environmental factors to the observed phenotypes as they relate to susceptibility/resistance to re-infection and disease states. We will then test hypotheses regarding sources of variation in immunological phenotypes associated both with susceptibility/resistance to re-infection and the clinical outcomes using maximum likelihood variance component methods. Variance components methods will allow us to partition the variance in a trait among components attributable to genetic factors, systematic environmental factors (e.g., water contact), and random environmental factors (unknown factors). Finally, we will perform linkage analysis and combined linkage/disequilibrium analysis to determine the contribution of candidate genes involved in determining the expression of immunological phenotypes related to susceptibility/resistance to re-infection and disease outcomes. The proposed project is a first step to demonstrate that host genetic factors are indeed involved in schistosome-human interactions. The ultimate goal of our genetic epidemiologic study is to identify and localize specific genes influencing infection and disease in schistosomiasis. We expect to improve our understanding of the underlying genetic determinants of resistance to reinfection with schistosomiasis and disease progression.