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Transcription Factor Binding Site Polymorphisms within DIO2 and GADD45A genes increase the risk of liver disease progression in chronic hepatitis b carriers

ABSTRACT: The aim of this study was to determine the association of single nucleotide polymorphisms (SNPs) within transcription factor binding sites with the progression of liver damage in chronic hepatitis B patients. The study group consisted of 284 chronic hepatitis B (CHB) patients, including individuals with mild fibrosis (32.5%), moderate to severe fibrosis (27.5%), liver cirrhosis – LC (22%), hepatocellular carcinoma – HCC (5%), and no fibrosis (13%) participants. SNP genotyping was performed by mass spectrometry, and included SNPs: DIO2 (rs225017, rs225014), PPARG (rs10865710, rs2016520), ATF3 (rs11119982), AKT3 (rs12031994), and GADD45A (rs532446, rs37834688), TBX21 (rs4794067). The patients’ susceptibility to advanced liver fibrosis was independly associated with rs225014 TT (DIO2) and rs10865710 CC (PPARG), whereas cirrhosis occurrence was more common in individuals with GADD45A rs532446 TT, and ATF3 rs11119982 TT genotypes. Moreover, DIO2 rs225014 CC variant was more common patients with diagnosed hepatocellular carcinoma (HCC). These results suggest the potential role of above SNPs in HBV-induced liver damage in a Caucasian population.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST1042 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:UNLABELLED:The microRNA miR-122 is highly expressed in the liver and stimulates hepatitis C virus (HCV) replication in vitro. IFNL3 (lambda-3 interferon gene) polymorphisms and the expression of miR-122 have been associated with sustained virological response (SVR) to treatment with pegylated interferon plus ribavirin in patients with chronic hepatitis C (CHC). We investigated, in vivo, the relationship between miR-122 expression, IFNL3 polymorphism, fibrosis, and response to PEG-IFN plus ribavirin. Pretreatment liver biopsy specimens and serum samples from 133 patients with CHC were included. Sixty-six patients achieved SVR, and 64 failed to respond to the treatment (43 nonresponders [NR] and 21 relapsers [RR]). All stages of fibrosis were represented, with 39, 50, 23, and 19 patients, respectively, having Metavir scores of F1, F2, F3, and F4. miR-122 expression was assessed by real-time quantitative PCR (RT-qPCR) and IFNL3 rs12979860 by direct sequencing. Hepatic miR-122 expression was higher in patients with the IFNL3 CC genotype than in those with the IFNL3 CT or TT genotype, in all patients (P = 0.025), and in NRs plus RRs (P = 0.013). Increased hepatic miR-122 was more strongly associated with complete early virological response (cEVR) (P = 0.003) than with SVR (P = 0.016). In multivariate analysis, increased hepatic miR-122 was only associated with the IFNL3 CC genotype. miR-122 was decreased in patients with advanced fibrosis (Metavir scores of F3 and F4) compared to its levels in patients with mild and moderate fibrosis (F1 and F2) (P = 0.01). Serum and hepatic expression of miR-122 were not associated. The association between miR-122 and IFNL3 was stronger than the association between miR-122 and response to treatment. miR-122 may play a role in the early viral decline that is dependent on IFNL3 and the innate immune response. IMPORTANCE:miR-122 plays a crucial role during HCV infection. Moreover, it was reported that miR-122 binding within the HCV genome stimulates its replication. Moreover, miR-122 is highly expressed within hepatocytes, where it regulates many cellular pathways. A reduction of miR-122 expression has been suggested to be associated with responsiveness to IFN-based therapy in patients with chronic hepatitis C. Several independent genome-wide association studies reported a strong association between IFNL3 polymorphism and responsiveness to IFN-based therapy. We report here a strong association between the expression of miR-122 and IFNL3 polymorphism that is independent of the response to the treatment. Our data suggest that modification of miR-122 expression may play an important role in the molecular mechanism associated with IFNL3 polymorphism. Moreover, we report a reduction of miR-122 at more advanced stages of fibrosis in patients with chronic hepatitis C.

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Transcription Factor Binding Site Polymorphisms within DIO2 and GADD45A genes increase the risk of liver disease progression in chronic hepatitis b carriers

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