Role of cytokine gene polymorphism in recurrent HCV infection after liver transplantation


Role of Cytokine Gene Polymorphism in Recurrent HCV Infection After Liver Transplantation


We read with interest the work by Kimball and colleagues, “Allograft TNFβ and IL16 Polymorphisms Influence HCV Recurrence and Severity After Liver Transplantation,” which appears in the February 2006 issue of Liver Transplantation.1 We would like to add a finding from our recent study that may shed more light on the mechanisms underlying the accelerated and aggressive course of hepatitis C virus (HCV) infection and the rapid progression of fibrosis in liver transplant recipients compared to immune-competent individuals.2

Most patients acquire recurrent HCV within 5 years of transplantation. However, some maintain minimal to moderate liver damage, whereas others advance rapidly to end-stage disease and graft failure.2, 3 The rate of progression is affected by a range of virus-, host-, and environment-related variables4: donor and recipient age, sex, and histocompatibility; year of transplantation; pretransplantation HCV RNA levels; viral genotype and quasispecies; use of immunosuppressive agents; and histological findings on the first liver biopsy.

Allograft tumor necrosis factor (TNF)-β and interleukin (IL)-16 gene polymorphisms correlated with the l-year clinical outcome in HCV-positive recipients. In their recent study, Kimball et al.1 reported that recipients of donor TNF-β2,2 experienced less recurrence (P < 0.05), less fibrosis (P < 0.01), and less rejection (P < 0.01) than recipients of donor TNF-β1,1. Recipients of donor TNF-β1,2 demonstrated an intermediate picture, with less fibrosis (P < 0.01) and less rejection (P < 0.01) than TNF-β1,1 recipients. Recipients of donor IL16TC showed less recurrence (P < 0.05), less fibrosis (P < 0.06), and less rejection (P < 0.06) than recipients of IL16TT genotype. Recipients of the combination TNF-β2,2/IL16TC donor genotype had the most benign clinical outcome, with less recurrence (P < 0.01), no fibrosis (P < 0.001), and fewer rejections (P < 0.01) than donor TNF-β1,1/IL16TT recipients. The authors concluded that allograft TNF-β and IL16 gene polymorphisms may be useful predictors of the severity of disease recurrence among HCV-positive patients after liver transplantation.

Platelet-derived growth factor (PDGF) is reportedly involved in the pathogenesis of liver fibrosis. In the liver, PDGF is released by inflammatory cells and promotes the proliferation of hepatic stellate cells (HSCs), the main source of extracellular matrix proteins. During hepatic fibrogenesis, PDGF is overexpressed,5 and the HSCs undergo a process of activation, developing a myofibroblast-like phenotype6 associated with increased proliferation and collagen synthesis. PDGF-B is the best-characterized chemotactic factor for HSCs and is recognized as their most potent mitogen. In a recently published study,7 we evaluated the possible association of molecular variants in the gene encoding PDGF-B with the risk of developing recurrent HCV infection after liver transplantation and with its severity. A statistically significant difference was observed in the distribution of the PDGF-B gene polymorphism at position +1135, but not +286, between patients and controls (P = 0.05). The A/A genotype occurred at a highly significantly increased rate in patients with recurrent HCV infection than in those without (P = 0.0001) and in patients with severe recurrence than in those with nonsevere recurrence (P = 0.05). The expression level of intrahepatic PDGF-B was highly correlated with the fibrosis stage (P < 0.0001). Further analysis yielded a highly statistically significant relationship between the PDGF-B gene polymorphism at position +1135 and clinical parameters of disease severity. Our data emphasize the potential importance of PDGF-B gene polymorphism in recurrent severe HCV infection and the role of PDGF-B in the development and progression of hepatic fibrosis.

Thus, cytokine gene polymorphisms may serve as candidate predictive factors for the severity of HCV recurrence after liver transplantation. These findings, if confirmed in further studies, might have important implications for patient selection for therapy and for the design of preventive measures.

Ziv Ben-Ari*, * Liver Institute and Department of Medicine D, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, Israel.