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Interferon Lambda Polymorphisms Associate with Body Iron Indices and Hepatic Expression of Interferon-Responsive Long Non-Coding RNA in Chronic Hepatitis C

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Interferon Lambda Polymorphisms Associate with Body Iron Indices and Hepatic Expression of Interferon-Responsive Long Non-Coding RNA in Chronic Hepatitis C Clin Exp Med DOI 10.1007/s10238-016-0423-4 ORIGINAL ARTICLE Interferon lambda polymorphisms associate with body iron indices and hepatic expression of interferon-responsive long non-coding RNA in chronic hepatitis C 1 1 1 2 Anna Wro´blewska • Agnieszka Bernat • Anna Woziwodzka • Joanna Markiewicz • 1 1 3 Tomasz Romanowski • Krzysztof P. Bielawski • Tomasz Smiatacz • Katarzyna Sikorska3,4 Received: 4 March 2016 / Accepted: 18 April 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Single nucleotide polymorphisms (SNPs) within markers of serum and hepatocyte iron overload associated DNA region containing interferon lambda 3 (IFNL3) and with higher activity of gamma-glutamyl transpeptidase and IFNL4 genes are prognostic factors of treatment response liver steatosis. The presence of two minor alleles in any of in chronic hepatitis C (CHC). Iron overload, frequently the tested SNPs predisposed to abnormally high serum iron diagnosed in CHC, is associated with unfavorable disease concentration and correlated with higher hepatic expres- course and a risk of carcinogenesis. Its etiology and rela- sion of lncRNA NRIR. On the other hand, homozygosity in tionship with the immune response in CHC are not fully any major allele associated with higher viral load. Patients explained. Our aim was to determine whether IFNL poly- bearing rs12979860 CC genotype had lower hepatic morphisms in CHC patients associate with body iron expression of hepcidin (HAMP; P = 0.03). HAMP mRNA indices, and whether they are linked with hepatic expres- level positively correlated with serum iron indices and sion of genes involved in iron homeostasis and IFN sig- degree of hepatocyte iron deposits. IFNL polymorphisms naling. For 192 CHC patients, four SNPs within IFNL3- influence regulatory pathways of cellular response to IFN IFNL4 region (rs12979860, rs368234815, rs8099917, and affect body iron balance in chronic hepatitis C virus rs12980275) were genotyped. In 185 liver biopsies, infection. histopathological analyses were performed. Expression of five mRNAs and three long non-coding RNAs (lncRNAs) Keywords Hepatitis C, chronic Á Interferon lambda Á Iron was determined with qRT-PCR in 105 liver samples. overload Á Polymorphism, single nucleotide Á RNA, long Rs12979860 TT or rs8099917 GG genotypes as well as non-coding Electronic supplementary material The online version of this article (doi:10.1007/s10238-016-0423-4) contains supplementary Introduction material, which is available to authorized users. Chronic hepatitis C virus (HCV) infection affects more & Katarzyna Sikorska [email protected] than 170 million people worldwide. Liver cirrhosis and hepatocellular carcinoma which develop as a consequence 1 Laboratory of Molecular Diagnostics, Intercollegiate Faculty of chronic hepatitis C (CHC) are the leading causes of of Biotechnology UG and MUG, Abrahama 58, death in western countries. It is expected that HCV-related 80-307 Gdan´sk, Poland 2 morbidity will increase during next 10–20 years [1]. Department of Infectious Diseases, Pomeranian Center of In 2009, genome-wide associations studies identified Infectious Diseases, Smoluchowskiego 18, 80-214 Gdan´sk, Poland three single nucleotide polymorphisms (SNPs) within DNA region containing interferon lambda 3 (IFNL3) and IFNL4 3 Department of Infectious Diseases, Medical University of Gdansk, Smoluchowskiego 18, 80-214 Gdan´sk, Poland genes, rs12979860, rs809917 and rs12980275, as prog- nostic factors of HCV-related liver disease, strongly asso- 4 Department of Tropical Medicine and Epidemiology, Medical University of Gdansk, Powstania Styczniowego 9b, ciated with treatment-induced and spontaneous clearance 81-519 Gdynia, Poland of HCV [2–4]. Homozygosity in the major rs12979860 C 123 Clin Exp Med allele in CHC patients correlates with a higher baseline sequence, was suggested to have a pivotal role in the viral load, lower expression of interferon-stimulated genes development of iron overload syndrome in CHC [14, 18]. (ISGs) [5] and an increased rate of sustained virological Hepcidin gene (HAMP) expression is regulated in response response (SVR) [6]. Additionally IFNL3-IFNL4 SNP to changes in body iron as well as by inflammatory variants are linked with metabolic abnormalities observed cytokines, hypoxia and growth signals [19]. Many reports in CHC. The beneficial rs12979860 CC and rs8099917 TT show lower hepatic HAMP expression in CHC patients [14, genotypes are associated with a lower incidence of hepatic 18, 20–22], and this downregulation may be due to HCV- steatosis, higher serum LDL and total cholesterol levels in induced oxidative stress which inhibits transcription factor CHC but also with higher probability of hepatic inflam- C/EBPalpha [21]. mation and fibrosis [7–9]. Recently a genetic variant Polymorphisms in IFNL3-IFNL4 gene region, which rs368234815 (ss469415590, DG/T) was found in strong impact the magnitude of cellular signaling in response to linkage disequilibrium (LD) with rs12979860. Patients HCV infection, are known predictors of CHC disease homozygous for T allele in rs368234815 show no expres- course and treatment outcome. Also the role of markers of sion of INFL4 due to a disrupted open reading frame, in iron overload is discussed in the context of liver fibrosis contrast to IFNL4-synthesizing carriers of the wild-type progression, the efficacy of antiviral treatment and risk of DG allele [10]. Hepatic expression of IFNL4 is specifically carcinogenesis in CHC [12–16]. The precise molecular induced upon HCV infection, and the presence of an active mechanisms linking IFNL SNPs and immune response to IFNL4 protein seems to be disadvantageous for disease HCV infection, as well as the elusive role of iron overload course. It was suggested that rs368234815 is the causal in the pathogenesis of CHC, are not completely under- SNP for the observed association between IFNL genotypes, stood. This knowledge is important, as it could be used to HCV clearance and therapeutic outcome in CHC [11]. establish new prognostic factors of HCV-related liver dis- Dysregulation of iron homeostasis, which is diagnosed ease. Moreover, modulation of iron balance could be in up to 40 % cases of CHC and 50 % cases with both considered as a potential target for adjuvant therapy of CHC and hepatocellular carcinoma, is associated with liver HCV infection. damage and correlates with a raised activity of amino- In this work, we investigated the association of IFNL transferases, exacerbation of inflammation, progression of polymorphisms in CHC patients with body iron indices, as liver fibrosis, increased risk of hepatocarcinogenesis, and a well as with hepatic expression of selected genes involved decrease in the effectiveness of antiviral therapy [12–16]. in iron homeostasis and immune response to HCV However, the relationship between elevated iron indices, infection. Among others, we measured the levels of three HCV life cycle, the profile of the host’s immune response long non-coding RNAs (lncRNAs), whose expression is and disease outcome remains unclear, and for several years known to be modulated in response to viral infection and it has been under intensive discussion with contradictory IFN treatment. One of these RNAs, lncRNA-CMPK2, reports being published. Based on experimental studies, called negative regulator of IFN response (NRIR), was high iron was suggested to be an element of antiviral previously significantly induced by IFN alpha (IFNA) and defense, potentially limiting HCV replication in CHC [17]. IFN gamma, but not by tumor necrosis factor alpha On the contrary, presence of iron overload markers is (TNFA)invariouscelllines,aswellasinHCV-infected connected with resistance to IFN therapy and many studies human livers [23]. This lncRNA was shown to act through suggest that iron depletion through phlebotomies is an suppression of transcription of a subset of interferon- effective strategy of improving liver status and IFN treat- stimulated genes (ISGs) and to affect HCV replication. ment efficacy in CHC patients [13, 15]. Also the genesis Another regulatory lncRNA, named a negative regulator and individual predisposition to development of iron of antiviral response (NRAV), was found to be down- overload condition in CHC are still unknown. HFE gene regulated in response to infection with several viruses. mutations appeared to be the main causative agent of NRAV interacts with ZONAB transcription factor and inherited iron overload among Caucasians, defined as inhibits expression of several antiviral effectors of innate hereditary hemochromatosis. Although the presence of immunity such as MxA or IFITM3 [24]. Expression of mutant C282Y allele in HFE protein is known to be BST2 IFN-stimulated positive regulator (BISPR) is associated with elevated serum markers of iron metabolism upregulated in livers of HCV-infected patients, and in and iron tissue accumulation in CHC, HFE mutations cells treated with IFNA2 or IFNL, but not with TNFA, cannot be considered a major factor leading to iron over- and positively regulates expression of BST2,which load in HCV-infected subjects [16]. Hepcidin, a 25-aa encodes antiviral protein, tetherin [25]. peptide hormone engaged in the control of body iron In this report for the first time, we show an association homeostasis, which is encoded by a gene located on of IFNL genotypes, indices of systemic iron balance, as chromosome 19q13, 13.8 kbp upstream from IFNL3 well as hepatic expression of HAMP and an IFN-responsive 123 Clin Exp Med lncRNA,
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