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IFN- Polymorphisms (IFN- +2109 and IFN- +3810) Are Associated with Severe Hepatic Fibrosis in Human Hepatic Schistosomiasis (Schistosoma mansoni) ¹

Christophe Chevillard^2,3,*, Carole Eboumbou Moukoko^2,*, Nasr-Eldin M. A. Elwali, Jay H. Bream^4,, Bourema Kouriba^*, Laurent Argiro^*, Siddig Rahoud, Adil Mergani, Sandrine Henri^*, Jean Gaudart^*, Qurashi Mohamed-Ali, Howard A. Young and Alain J. Dessein^*

^* Immunologie et Génétique des Maladies Parasitaires, Laboratoire de Parasitologie-Mycologie, Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale Unité 399, Marseille, France; Institute of Nuclear Medicine, Molecular Biology and Oncology, University of Gezira, Wad Medani, Sudan; Laboratory of Experimental Immunology, National Cancer Institute, Frederick, MD 21702; and Al Zaiem Al Azhari University, Omdurman, Sudan

Schistosome infection is a major public health concern affecting millions of people living in tropical regions of Africa, Asia, and South America. Schistosomes cause mild clinical symptoms in most subjects, whereas a small proportion of individuals presents severe clinical disease (as periportal fibrosis (PPF)) that may lead to death. Severe PPF results from an abnormal deposition of extracellular matrix proteins in the periportal spaces due to a chronic inflammation triggered by eggs and schistosome Ags. Extracellular matrix protein production is regulated by a number of cytokines, including IFN-. We have now screened putative polymorphic sites within this gene in a population living in an endemic area for Schistosoma mansoni. Two polymorphisms located in the third intron of the IFN- gene are associated with PPF. The IFN- +2109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN- +3810 G/A polymorphism is associated with less PPF. The polymorphisms result in changes in nuclear protein interactions with the intronic regions of the gene, suggesting that they may modify IFN- mRNA expression. These results are consistent with the results of previous studies. Indeed, PPF is controlled by a major locus located on chromosome 6q22-q23, closely linked to the gene encoding the -chain of the IFN- receptor, and low IFN- producers have been shown to have an increased risk of severe PPF. Together, these observations support the view that IFN- expression and subsequent signal transduction play a critical role in the control of PPF in human hepatic schistosome infection (S. mansoni).

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