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.
Highlights
Chronic hepatitis C virus (HCV) infection affects more than 170 million people worldwide
Our aim was to determine whether IFNL polymorphisms in chronic hepatitis C (CHC) patients associate with body iron indices, and whether they are linked with hepatic expression of genes involved in iron homeostasis and IFN signaling
We investigated the association of IFNL polymorphisms in CHC patients with body iron indices, as well as with hepatic expression of selected genes involved in iron homeostasis and immune response to HCV infection
Summary
Chronic hepatitis C virus (HCV) infection affects more than 170 million people worldwide. In 2009, genome-wide associations studies identified three single nucleotide polymorphisms (SNPs) within DNA region containing interferon lambda 3 (IFNL3) and IFNL4 genes, rs12979860, rs809917 and rs12980275, as prognostic factors of HCV-related liver disease, strongly associated with treatment-induced and spontaneous clearance of HCV [2,3,4]. IFNL3-IFNL4 SNP variants are linked with metabolic abnormalities observed in CHC. Hepatic expression of IFNL4 is induced upon HCV infection, and the presence of an active IFNL4 protein seems to be disadvantageous for disease course. It was suggested that rs368234815 is the causal SNP for the observed association between IFNL genotypes, HCV clearance and therapeutic outcome in CHC [11]
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