Interferon lambda polymorphisms associate with body iron indices and hepatic expression of interferon-responsive long non-coding RNA in chronic hepatitis C

Abstract

Single nucleotide polymorphisms (SNPs) within DNA region containing interferon lambda 3 (IFNL3) and IFNL4 genes are prognostic factors of treatment response in chronic hepatitis C (CHC). Iron overload, frequently diagnosed in CHC, is associated with unfavorable disease course and a risk of carcinogenesis. Its etiology and relationship with the immune response in CHC are not fully explained. Our aim was to determine whether IFNL polymorphisms in CHC patients associate with body iron indices, and whether they are linked with hepatic expression of genes involved in iron homeostasis and IFN signaling. For 192 CHC patients, four SNPs within IFNL3-IFNL4 region (rs12979860, rs368234815, rs8099917, rs12980275) were genotyped. In 185 liver biopsies, histopathological analyses were performed. Expression of five mRNAs and three long non-coding RNAs (lncRNAs) was determined with qRT-PCR in 105 liver samples. Rs12979860 TT or rs8099917 GG genotypes as well as markers of serum and hepatocyte iron overload associated with higher activity of gamma-glutamyl transpeptidase and liver steatosis. The presence of two minor alleles in any of the tested SNPs predisposed to abnormally high serum iron concentration and correlated with higher hepatic expression of lncRNA NRIR. On the other hand, homozygosity in any major allele associated with higher viral load. Patients bearing rs12979860 CC genotype had lower hepatic expression of hepcidin (HAMP; P = 0.03). HAMP mRNA level positively correlated with serum iron indices and degree of hepatocyte iron deposits. IFNL polymorphisms influence regulatory pathways of cellular response to IFN and affect body iron balance in chronic hepatitis C virus infection.Electronic supplementary materialThe online version of this article (doi:10.1007/s10238-016-0423-4) contains supplementary material, which is available to authorized users.

Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker

“…Hepcidin expression during HCV infection is complicated by the effect of genetic factors. These factors have been shown to predispose patients with HCV to a different treatment potential of anti-HCV drugs (Wróblewska et al 2017 ).…”

The iron homeostasis network and hepatitis C virus – a new challenge in the era of directly acting antivirals

“…Recently, we have confirmed an interesting link between favorable, prognostic immune profile associated with single nucleotide polymorphism (SNP) encoding interferon lambda 3 (rs12979860 CC) with lower serum iron and ferritin, and decreased hepatic expression of hepcidin and some interferon stimulated genes in CHC patients. 24 This SNP associates with a better response to treatment with interferon and a higher chance for spontaneous HCV elimination. These observations in vivo are compatible with the results by Foka et al They may serve for better understanding of host-virus interactions and the links between virulence of HCV, iron metabolism and immune response in HCV-related disease.…”

Reduced ITPase activity and favorable IL28B genetic variant protect against ribavirin-induced anemia in interferon-free regimens

“…Although the precise molecular mechanism linking the rs12979860 SNP to IFN/RBV response has not been identified, its impact on immune function in response to HCV infection has been demonstrated. Additionally, there was an association of IFNL genotype with systemic iron balance, which may play a role in impacting peripheral iron status[ 37 ]. A recent paper which described clinical trial simulations in a mathematical model of RBV-induced anemia in HCV patients suggested, in contrast to our observations, that the non-CC rs12979860 patients had the least severe anemia [ 38 ].…”