Research Article: Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C

Date Published: July 12, 2017

Publisher: Public Library of Science

Author(s): Rosario López-Rodríguez, Ángel Hernández-Bartolomé, María Jesús Borque, Yolanda Rodríguez-Muñoz, Samuel Martín-Vílchez, Luisa García-Buey, Leticia González-Moreno, Yolanda Real-Martínez, Paloma Muñoz de Rueda, Javier Salmerón, José Ramón Vidal-Castiñeira, Carlos López-Larrea, Luis Rodrigo, Ricardo Moreno-Otero, Paloma Sanz-Cameno, Matias A. Avila.


Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient’s genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients.

NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0–2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates.

Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.

Partial Text

Hepatitis C virus (HCV) is a major cause of liver-related morbidity and mortality, affecting 170 million people worldwide [1]. Natural history of chronic hepatitis C (CHC) is characterized by a highly variable progression and depending on the extent of liver fibrosis and inflammation CHC can progress to cirrhosis and hepatocellular carcinoma (HCC) [2]. Although new antiviral drugs are highly effective in eradicating HCV infection, there is an important percentage of patients in which the use of these therapies is restricted due to co-morbidities or socio-economic reasons [3]. Moreover, recent studies suggest that virus clearance, especially at advanced stages of disease, does not definitively guarantee healing of liver injury and neither abrogates the risk of liver decompensation or HCC development [4–6]. Therefore, the identification of non-invasive biomarkers that accurately predict the evolution of the disease might notably improve the prevention and clinical management of these patients, especially in the view of unexpected elevated frequency of hepatic and extrahepatic events related to current interferon (IFN)-free therapy. The immune system plays a central role in the therapeutic response and in the appearance of various disorders associated with CHC [7,8], and several genome-wide association studies have revealed the strong association of IL-28B rs12979860 polymorphism with the attainment of sustained virological response (SVR) in patients treated with the conventional antiviral therapy (pegylated-interferon and ribavirin) [9–11]. Similarly, other SNPs located in interferon stimulated genes (ISGs) were also independently related to SVR improving the predictive value of IL-28B (rs12979860) for combination treatment outcome [12].

As known, HCV clearance, CHC progression and response to treatment is driven by multiple and complex interactions among host, viral and environmental factors [21]. Innate immunity constitutes the first line of defense against HCV infection and triggers the synthesis of interferons (IFNs), chief antiviral factors able to reprogram cellular status by the induction of multiple genes (IFN-stimulated genes, ISGs) which limit virus replication and the subsequent liver damage [22–24]. Therefore, host genetic polymorphisms in genes involved in IFN signaling may notably influence the onset and progression of the disease as has been demonstrated for IL-28B [9–11].




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