Abstract
Genetic polymorphisms in the region of the interferon-λ genes (IFNL) associate with clearance of hepatitis C virus (HCV) infection. One of these polymorphisms, IFNL4 rs368234815, determines loss or gain of function of the IFNL4 gene by frameshift variation. The very same and a second one, IFNL3 rs4803217, are supposed to impact the expression of IFNL3: while IFNL4 rs368234815 is suggested to modulate IFNL3 transcription, IFNL3 rs4803217 is thought to alter IFNL3 mRNA stability. The latter process is believed to be partially driven by an HCV-induced ectopic expression of myosin heavy chain genes 7B and 7 and their co-expressed microRNAs mir499 and mir208B. These ideas are evidenced by functional investigations on peripheral blood mononuclear and hepatoma cells in culture. Our study aimed at exploring IFNL3 gene expression in clinical samples, i.e., in ex vivo derived liver tissue from patients with chronic hepatitis C (n = 57) and various other diseases (n = 56). By applying an assay designed to specifically quantify IFNL3 and discriminating paralogous IFNL2 transcripts, IFNL3 mRNA expression was not found to differ significantly between chronic hepatitis C and control samples. Among patients with chronic HCV infection, moreover, IFNL3 rs4803217 or IFNL4 rs368234815 minor alleles did not associate with reduced IFNL3 gene expression. Finally, myosin heavy chain genes 7B and 7 and corresponding microRNAs mir499 and mir208B were not found activated in liver in chronic HCV infection. Of note, detectability of MYH7 mRNA related to the procedure of liver biopsy sampling, as tissue obtained by direct punctation of the liver during laparoscopic inspection was less likely to contain MYH7 transcripts than samples acquired by percutaneous punctation. In conclusion, data on ex vivo derived liver tissue samples argue against an attenuating impact of IFNL3 rs4803217 or IFNL4 rs368234815 minor alleles on hepatic IFNL3 gene expression in vivo.
Highlights
Infection with hepatitis C virus (HCV) affects an estimated 160 million people worldwide [1]
Liver biopsy specimens were obtained from a total of 113 patients of Western European descent with chronic hepatitis C (n = 57; see Table 1), chronic hepatitis B virus (HBV) infection (n = 18; males, four females; mean age 33.2 ± 11.0 years), non-viral liver diseases (n = 26; males, 11 females; mean age 47.5 ± 13.4 years) and patients in whom liver disease could be ruled out by biopsy (n = 12; six males and females each; mean age 48.1 ± 18.3 years)
The favorable major allele G of IFNL3 rs4803217 was closely correlated to the favorable IFNL4 disrupting allele TT of IFNL4 ss469415590. 5/57 patients were found to be discordant at these two loci, yielding linkage disequilibrium (LD) coefficients of D’ = 0.887 and r2 = 0.7862
Summary
Infection with hepatitis C virus (HCV) affects an estimated 160 million people worldwide [1]. It causes chronic and progressive liver disease. In 2009, genome-wide association studies on main ethnic populations most convincingly have identified genetic variations in the region of the type III interferon-λ (IFN-λ/IFNL) genes to be correlated with clearance of infection [2,3,4,5]. Genetic associations were proved to be true for spontaneous clearance of HCV infection, for response to an IFN-α based therapy in patients with chronic hepatitis C and for regimens with a novel group of HCV-specific inhibitors, the direct acting antivirals [10,11,12]
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