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-gR1 gene encoding the receptor of the strongly
antifibrogenic cytokine interferon-g. 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-gR1 gene
could determine severe hepatic disease due to S. mansoni
infection and that the IFN-gR1 gene is a strong candidate
for the control of abnormal fibrosis observed in
other diseases.
