Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene

Lethal disease due to hepatic periportal fibrosis occurs in 2%-10% of subje cts infected by Schistosoma mansoni in endemic regions such as Sudan. It is unknown why few infected individuals present with severe disease, and inhe rited factors may play a role in fibrosis development. Schistosoma mansoni infection levels have been shown to be controlled by a locus that maps to c hromosome 5q31-q33. To investigate the genetic control of severe hepatic fi brosis (assessed by ultrasound examination) causing portal hypertension, a segregation analysis was performed in 65 Sudanese pedigrees from the same v illage. Results provide evidence for a codominant major gene, with .16 as t he estimated allele A frequency predisposing to advanced periportal fibrosi s. 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 o ther subjects the penetrance remains <.02 after 20 years of exposure. Linka ge 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-gamma RI 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 controll ed by distinct loci; they suggest that polymorphisms within the IFN-gamma R 1 gene could determine severe hepatic disease due to S. mansoni infection a nd that the IFN-gamma R1 gene is a strong candidate for the control of abno rmal fibrosis observed in other diseases.