Severe Hepatic Fibrosis in Schistosoma mansoni Infection Is Controlled by a Major Locus That Is Closely Linked to the Interferon-γ 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.

Cytokine profile associated with chronic and acute human schistosomiasis mansoni

“…A genetic study suggested that IFN-γ is been associated with protection against severe portal fibrosis. The study mapped a locus on chromosome 6 which has been linked to a high risk of severe hepatic fibrosis, close to the IFN-γR gene (Dessein et al 1999, Booth et al 2004. Moreover, Fig.…”

Repeated Exposure Induces Periportal Fibrosis inSchistosoma mansoni-Infected Baboons: Role of TGF-β and IL-4

“…In contrast, IL-2 and IFN-␥ failed to correlate with fibrosis. These cytokines have been implicated in the induction and down-modulation of fibrosis, respectively (13,18,19,38), and the recent observation that severe hepatic fibrosis in humans may be regulated, in part, by a locus that is closely linked to the gene encoding IFN-␥R1 (8).…”

Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in South India

“…For example, in schistosomiasis, genetic loci for susceptibility and resistance have been physically mapped. [15][16][17][18][19][20][21] Since there have been relatively few investigations of the host genetic contribution to acquisition and outcomes in human filarial infection, we performed a pilot study, utilizing a candidate gene approach. The chosen genes fulfilled the following criteria: a frequency of greater than 5% of at least one polymorphic variant in one or more populations, in vitro evidence of the biological significance of the variant and prior clinical studies suggesting a role in disease susceptibility or outcome.…”