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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041680-03
Application #
2887527
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Hall, B Fenton
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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