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

Abstract

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-γ. 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-γ gene are associated with PPF. The IFN-γ +2109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-γ +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-γ 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 α-chain of the IFN-γ receptor, and low IFN-γ producers have been shown to have an increased risk of severe PPF. Together, these observations support the view that IFN-γ expression and subsequent signal transduction play a critical role in the control of PPF in human hepatic schistosome infection (S. mansoni).

Single Nucleotide Polymorphisms of Cytokine Genes are Associated with Fibrosis of the Intrahepatic Bile Duct Wall in Human Clonorchiasis

“…A study on IFN-γgene polymorphism associated with Schistosoma mansoni liver pathology revealed that, +2,109 A/G genotype promoted hepatic fibrosis and +3,810 G/A genotype inhibited it [15]. Our study suggests that +874AT genotype of IFN-γmay play a key role for bile duct fibrosis in clonorchiasis.…”

Association of Type 2 Cytokines with Hepatic Fibrosis in HumanSchistosoma mansoniInfection

“…A recent study has found a protective effect of IFN-␥ in liver fibrosis in Sudanese S. mansoni-infected subjects (16). The same group has also described an association between severe hepatic fibrosis with a polymorphic allele of the IFN-␥ gene involved in reduced IFN-␥ production (7). Another recent study has also associated low IFN-␥ production with liver fibrosis (4).…”

Avaliação das citocinas IL-10 e IL-13 como mediadores na progressão da fibrose de Symmers em portadores de esquistossomose mansônica na forma hepatoesplênica

“…Association was found between the levels of infection and the region 5q31 q33 20 , in which the IL13 gene is located. Polymorphisms in the promoter region of this gene were associated with high frequency of infection 21 .Studies in patients with severe periportal fibrosis associated with Brandt Brandt Brandt Brandt Brandt Evaluation of the cytokines IL-10 and IL-13 as mediators in the progression of symmers fibrosis in patients with hepatosplenic schistosomiasis mansoni portal hypertension detected significant association of regions 6q22-q23 22 and 12q24 23 in the susceptibility/ resistance to developing this phenotype. Polymorphisms in the genes IFNGR1 (6q22-q23), which codes the á chain of the IFN-ã receptor 22 and IFNG (12q24) 23 were found to be associated as well.…”