HOST GENETIC CORRELATES IN SCHISTOSOMIASIS

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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.