title: 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.
authors.affiliation: Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wróblewska
authors.affiliation: Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bernat
authors.affiliation: Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Woziwodzka
authors.affiliation: Department of Infectious Diseases, Pomeranian Center of Infectious Diseases, Smoluchowskiego 18, 80-214, Gdańsk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Markiewicz
authors.affiliation: Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Romanowski
authors.affiliation: Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland.
authors.forename: Krzysztof P
authors.initials: KP
authors.lastname: Bielawski
authors.affiliation: Department of Infectious Diseases, Medical University of Gdansk, Smoluchowskiego 18, 80-214, Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Smiatacz
authors.affiliation: Department of Infectious Diseases, Medical University of Gdansk, Smoluchowskiego 18, 80-214, Gdańsk, Poland. ksikorska@gumed.edu.pl.|Department of Tropical Medicine and Epidemiology, Medical University of Gdansk, Powstania Styczniowego 9b, 81-519, Gdynia, Poland. ksikorska@gumed.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sikorska
mesh_terms: D000328:Adult; D001706:Biopsy; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000473:pathology; D006651:Histocytochemistry; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D019190:Iron Overload / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; D062085:RNA, Long Noncoding; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human
keywords: Hepatitis C, chronic; Interferon lambda; Iron overload; Polymorphism, single nucleotide; RNA, long non-coding