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

Hugo R. Rosen, Jennifer J. Lentz, Steven L. Rose, John Rabkin, Christopher Corless, Kent Taylor, Sunwen Chou

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background. Hepatitis C-related liver failure is the leading indication for liver transplantation Worldwide. Although histologic recurrence is identified 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) recurrence. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable 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 reaction amplification, followed by sequencing for two promoter TNF-α variants (at positions -238 and -308), and restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, and aa26). Results. The relative prevalence of polymorphisms corresponded to distributions previously reported in normal control populations. Twenty-two of 31 (71%) patients received a donor liver homozygous for the wild type allele (TNF1) at the -308 TNF-α promoter region. The interval to histologic recurrence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles. At last follow-up biopsy, 5 of 9 (56%) patients with a TNF308.2 donor liver had evidence of severe histological activity index as compared to 2 of 22 (9%) of 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 TNF-α or TNF-β alleles. TNF-β polymorphisms within the donor liver did not correlate with severity of HCV recurrence. Conclusions. The donor TNF-α promoter genotype may influence the inflammatory response to HCV reinfection of the graft and contribute to accelerated 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.

Original languageEnglish (US)
Pages (from-to)1898-1902
Number of pages5
JournalTransplantation
Volume68
Issue number12
StatePublished - Dec 27 1999

Fingerprint

Hepatitis C
Liver Transplantation
Hepacivirus
Tumor Necrosis Factor-alpha
Tissue Donors
Recurrence
Genes
Alleles
Liver
Allografts
Transplants
Donor Selection
Inborn Genetic Diseases
Liver Failure
Wounds and Injuries
Genetic Polymorphisms
Genetic Markers
Genetic Promoter Regions
Immunosuppression
Hepatitis

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Donor polymorphism of tumor necrosis factor gene : Relationship with variable severity of hepatitis C recurrence after liver transplantation. / Rosen, Hugo R.; Lentz, Jennifer J.; Rose, Steven L.; Rabkin, John; Corless, Christopher; Taylor, Kent; Chou, Sunwen.

In: Transplantation, Vol. 68, No. 12, 27.12.1999, p. 1898-1902.

Research output: Contribution to journalArticle

Rosen, Hugo R. ; Lentz, Jennifer J. ; Rose, Steven L. ; Rabkin, John ; Corless, Christopher ; Taylor, Kent ; Chou, Sunwen. / Donor polymorphism of tumor necrosis factor gene : Relationship with variable severity of hepatitis C recurrence after liver transplantation. In: Transplantation. 1999 ; Vol. 68, No. 12. pp. 1898-1902.
@article{bf3398e5dd62415a8c324b665601d2e9,
title = "Donor polymorphism of tumor necrosis factor gene: Relationship with variable severity of hepatitis C recurrence after liver transplantation",
abstract = "Background. Hepatitis C-related liver failure is the leading indication for liver transplantation Worldwide. Although histologic recurrence is identified 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) recurrence. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable 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 reaction amplification, followed by sequencing for two promoter TNF-α variants (at positions -238 and -308), and restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, and aa26). Results. The relative prevalence of polymorphisms corresponded to distributions previously reported in normal control populations. Twenty-two of 31 (71{\%}) patients received a donor liver homozygous for the wild type allele (TNF1) at the -308 TNF-α promoter region. The interval to histologic recurrence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles. At last follow-up biopsy, 5 of 9 (56{\%}) patients with a TNF308.2 donor liver had evidence of severe histological activity index as compared to 2 of 22 (9{\%}) of 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 TNF-α or TNF-β alleles. TNF-β polymorphisms within the donor liver did not correlate with severity of HCV recurrence. Conclusions. The donor TNF-α promoter genotype may influence the inflammatory response to HCV reinfection of the graft and contribute to accelerated 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.",
author = "Rosen, {Hugo R.} and Lentz, {Jennifer J.} and Rose, {Steven L.} and John Rabkin and Christopher Corless and Kent Taylor and Sunwen Chou",
year = "1999",
month = "12",
day = "27",
language = "English (US)",
volume = "68",
pages = "1898--1902",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

TY - JOUR

T1 - Donor polymorphism of tumor necrosis factor gene

T2 - Relationship with variable severity of hepatitis C recurrence after liver transplantation

AU - Rosen, Hugo R.

AU - Lentz, Jennifer J.

AU - Rose, Steven L.

AU - Rabkin, John

AU - Corless, Christopher

AU - Taylor, Kent

AU - Chou, Sunwen

PY - 1999/12/27

Y1 - 1999/12/27

N2 - Background. Hepatitis C-related liver failure is the leading indication for liver transplantation Worldwide. Although histologic recurrence is identified 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) recurrence. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable 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 reaction amplification, followed by sequencing for two promoter TNF-α variants (at positions -238 and -308), and restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, and aa26). Results. The relative prevalence of polymorphisms corresponded to distributions previously reported in normal control populations. Twenty-two of 31 (71%) patients received a donor liver homozygous for the wild type allele (TNF1) at the -308 TNF-α promoter region. The interval to histologic recurrence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles. At last follow-up biopsy, 5 of 9 (56%) patients with a TNF308.2 donor liver had evidence of severe histological activity index as compared to 2 of 22 (9%) of 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 TNF-α or TNF-β alleles. TNF-β polymorphisms within the donor liver did not correlate with severity of HCV recurrence. Conclusions. The donor TNF-α promoter genotype may influence the inflammatory response to HCV reinfection of the graft and contribute to accelerated 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.

AB - Background. Hepatitis C-related liver failure is the leading indication for liver transplantation Worldwide. Although histologic recurrence is identified 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) recurrence. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable 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 reaction amplification, followed by sequencing for two promoter TNF-α variants (at positions -238 and -308), and restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, and aa26). Results. The relative prevalence of polymorphisms corresponded to distributions previously reported in normal control populations. Twenty-two of 31 (71%) patients received a donor liver homozygous for the wild type allele (TNF1) at the -308 TNF-α promoter region. The interval to histologic recurrence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles. At last follow-up biopsy, 5 of 9 (56%) patients with a TNF308.2 donor liver had evidence of severe histological activity index as compared to 2 of 22 (9%) of 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 TNF-α or TNF-β alleles. TNF-β polymorphisms within the donor liver did not correlate with severity of HCV recurrence. Conclusions. The donor TNF-α promoter genotype may influence the inflammatory response to HCV reinfection of the graft and contribute to accelerated 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.

UR - http://www.scopus.com/inward/record.url?scp=0033611143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033611143&partnerID=8YFLogxK

M3 - Article

C2 - 10628771

AN - SCOPUS:0033611143

VL - 68

SP - 1898

EP - 1902

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 12

ER -