title: Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene.
abstract: Lethal disease due to hepatic periportal fibrosis occurs in 2%-10% of subjects infected by Schistosoma mansoni in endemic regions such as Sudan. It is unknown why few infected individuals present with severe disease, and inherited factors may play a role in fibrosis development. Schistosoma mansoni infection levels have been shown to be controlled by a locus that maps to chromosome 5q31-q33. To investigate the genetic control of severe hepatic fibrosis (assessed by ultrasound examination) causing portal hypertension, a segregation analysis was performed in 65 Sudanese pedigrees from the same village. Results provide evidence for a codominant major gene, with.16 as the estimated allele A frequency predisposing to advanced periportal fibrosis. For AA males, AA females, and Aa males a 50% penetrance is reached after, respectively, 9, 14, and 19 years of residency in the area, whereas for other subjects the penetrance remains <.02 after 20 years of exposure. Linkage analysis performed in four candidate regions shows that this major locus maps to chromosome 6q22-q23 and that it is closely linked (multipoint LOD score 3.12) to the IFN-gammaR1 gene encoding the receptor of the strongly antifibrogenic cytokine interferon-gamma. These results show that infection levels and advanced hepatic fibrosis in human schistosomiasis are controlled by distinct loci; they suggest that polymorphisms within the IFN-gammaR1 gene could determine severe hepatic disease due to S. mansoni infection and that the IFN-gammaR1 gene is a strong candidate for the control of abnormal fibrosis observed in other diseases.
authors.affiliation: INSERM U.399, Immunology and Genetics of Parasitic Diseases, Faculty of Medicine, Marseille, France. Alain.Dessein@medecine.univ-mrs.fr
authors.forename: A J
authors.initials: AJ
authors.lastname: Dessein
authors.forename: D
authors.initials: D
authors.lastname: Hillaire
authors.forename: N E
authors.initials: NE
authors.lastname: Elwali
authors.forename: S
authors.initials: S
authors.lastname: Marquet
authors.forename: Q
authors.initials: Q
authors.lastname: Mohamed-Ali
authors.forename: A
authors.initials: A
authors.lastname: Mirghani
authors.forename: S
authors.initials: S
authors.lastname: Henri
authors.forename: A A
authors.initials: AA
authors.lastname: Abdelhameed
authors.forename: O K
authors.initials: OK
authors.lastname: Saeed
authors.forename: M M
authors.initials: MM
authors.lastname: Magzoub
authors.forename: L
authors.initials: L
authors.lastname: Abel
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000469:parasitology; D008109:Liver Diseases, Parasitic / Q000150:complications* / Q000235:genetics / Q000469:parasitology; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D019683:Penetrance; D017471:Receptors, Interferon / Q000235:genetics*; D012555:Schistosomiasis mansoni / Q000150:complications* / Q000235:genetics / Q000469:parasitology; D012737:Sex Factors; D013397:Sudan; D013997:Time Factors; D014463:Ultrasonography; D000096743:Interferon gamma Receptor
chemical_list: D005819:Genetic Markers; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor