Interleukin-28B Polymorphisms Are Associated with Hepatic Fibrosis and Inflammatory Molecular Changes Following Liver Transplantation in Patients with Hepatitis C Infection
Stephen Osasan, Brad Thomas, Aldo Montano-Loza, Luis Hidalgo, Phil Halloran, Lorne Tyrell, Andrew Mason, Banu Sis. University of Alberta, Edmonton, AB, Canada
Background: Chronic hepatitis C is the leading indication for liver transplantation. Recurrence of hepatitis C after transplantation is universal and response rates to standard antiviral therapy are poor. Recently, genetic variation in the interleukin-28B (IL28B) gene, encoding interferon lambda3, has been associated with viral clearance in nontransplant and transplant patients. Histological and molecular consequences of this genetic variation are unknown. We aimed to gain further insight into effects of IL28B variants on hepatic tissue.
Design: We studied histopathology and large-scale gene expression by Affymetrix genechip in 25 liver transplant biopsies from 13 recipients with recurrent hepatitis C. Donor and recipient DNA were typed for IL28B gene polymorphisms rs12979860 and rs8099917 using ABI TagMan allelic discrimination kit. We related IL28B genotypes with histological activity, fibrosis stages, and gene expression profiles. We also related the transcripts to histopathology and clinical parameters.
Results: The frequencies of IL28B donor genotypes at rs12979860 were 5 C/C, 6 C/T, and 2 T/T and at rs8099917 8 T/T, 5 T/G, and 0 G/G. IL28B recipient genotyping is underway. The donor rs12979860 C/C genotype was related with higher histological hepatic fibrosis stages, portal inflammation, bile duct injury, and venulitis when compared to C/T and T/T genotypes. The donor rs8099917 T/T genotype was related with high fibrosis stages. Furthermore, rs12979860 C/C genotype was associated with increased intrahepatic expression of T cell and plasma cell (immunoglobulin) transcripts and decreased parenchymal transcripts, and rs8099917 T/T genotype is related with increased plasma cell transcripts. HCV viral loads were not different among IL28B genotypes. Ishak hepatitis activity scores strongly correlated with IFNG-dependent transcripts, T cell and macrophage-associated transcripts, and decreased liver transcripts. Indices of hepatocellular injury (ALT, AST, total bilirubin) were strongly correlated with increased IFNG-dependent transcripts and macrophage transcripts.
Conclusions: IL28B rs12979860 C/C and rs8099917 T/T genotypes are associated with more severe histological recurrence of hepatitis virus C infection with plasma cell rich infiltration. The molecular burden in liver biopsies reflects hepatitis C activity and fibrosis stage.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 256, Monday Morning