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

PLoS One. 2017 Jul 12;12(7):e0180927. doi: 10.1371/journal.pone.0180927. eCollection 2017.

Abstract

Introduction: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / genetics
  • Adult
  • Aged
  • Aspartate Aminotransferases / blood
  • Endoribonucleases / genetics
  • Female
  • Hepatitis C, Chronic / blood
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / pathology
  • Humans
  • Interferons
  • Interleukins / genetics*
  • Janus Kinase 1 / genetics
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • TYK2 Kinase / genetics

Substances

  • IFNL3 protein, human
  • Interleukins
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Interferons
  • Aspartate Aminotransferases
  • JAK1 protein, human
  • Janus Kinase 1
  • TYK2 Kinase
  • TYK2 protein, human
  • OAS1 protein, human
  • 2',5'-Oligoadenylate Synthetase
  • Endoribonucleases
  • 2-5A-dependent ribonuclease

Grant support

This work was supported by Ayudas Investigación Oncológica AIO-2010 to PSC (https://www.fundacioncientifica.aecc.es/); Ayudas Proyectos de Investigación Fundación Mutua Madrileña 2010 to RMO; Ayudas Proyectos de Investigación Fundación Mutua Madrileña 2012 to PSC (http://www.fundacionmutua.es/Ayudas-a-la-Investigacion.html); Programa Estatal de Investigación Fundamental Ministerio de Economía Industria y Competitividad SAF 2010-21805 to RMO (http://www.idi.mineco.gob.es/portal/site/MICINN/menuitem.dbc68b34d11ccbd5d52ffeb801432ea0/?vgnextoid=17aba53632295210VgnVCM1000001d04140aRCRD).