Donor polymorphism of tumor necrosis factor gene - Relationship with variable severity of hepatitis C recurrence after liver transplantation

Background. Hepatitis C-related liver failure is the leading indication for liver transplantation worldwide. Although histologic recurrence is identif ied in the majority of patients, the spectrum of allograft injury is wide. To date, most studies have focused on the contribution of immunosuppression and viral factors. We hypothesized that the allograft plays a significant role in determining timing and severity of hepatitis C virus (HCV) recurren ce. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly va riable severity of HCV recurrence. Methods. Thirty-one HCV-seropositive liver transplant recipients with long- term follow-up were studied. Genomic DNA was extracted from archived donor spleens which corresponded to each patient. We performed polymerase chain r eaction amplification, followed by sequencing for two promoter TNF-alpha va riants (at positions -238 and -308), and restriction fragment length analys is for four polymorphic loci within the TNF-beta gene (NcoI, TNFc, aa13, an d aa26). Results. The relative prevalence of polymorphisms corresponded to distribut ions previously reported in normal control populations. Twenty-two of 31 (7 1%) patients received a donor liver homozygous for the wild type allele (TN F1) at the -308 TNF-alpha promoter region. The interval to histologic recur rence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles, At las t follow-up biopsy, 5 of 9 (56%) patients with a TNF308.2 donor liver had e vidence of severe histological activity index as compared to 2 of 22 (9%) o f patients receiving a donor liver homozygous for the TNF1 allele (P=0.01). There was no correlation between rejection rates and the presence of any T NF-alpha or TNF-beta alleles. TNF-beta polymorphisms within the donor liver did not correlate with severity of HCV recurrence. Conclusions. The donor TNF-alpha promoter genotype may influence the inflam matory response to HCV reinfection of the graft and contribute to accelerat ed graft injury. If the association between this genetic marker (TNF308.2) and disease progression is confirmed, it could improve our understanding of HCV pathogenesis and influence donor selection and patient management.