Heme Oxygenase-1 Genotype of the Donor Is Associated With Graft Survival After Liver Transplantation

Abstract

Heme oxygenase-1 (HO-1) has been suggested as a cytoprotective gene during liver transplantation. Inducibility of HO-1 is modulated by a (GT) n polymorphism and a single nucleotide polymorphism (SNP) A(-413)T in the promoter. Both a short (GT) n allele and the A-allele have been associated with increased HO-1 promoter activity. In 308 liver transplantations, we assessed donor HO-1 genotype and correlated this with outcome variables. For (GT) n genotype, livers were divided into two classes: short alleles (<25 repeats; class S) and long alleles (≥25 repeats; class L). In a subset, hepatic messenger ribonucleic acid (mRNA) expression was correlated with genotypes. Graft survival at 1 year was significantly better for A-allele genotype compared to TT-genotype (84% vs. 63%, p = 0.004). Graft loss due to primary dysfunction (PDF) occurred more frequently in TT-genotype compared to A-receivers (p = 0.03). Recipients of a liver with TT-genotype had significantly higher serum transaminases after transplantation and hepatic HO-1 mRNA levels were significantly lower compared to the A-allele livers (p = 0.03). No differences were found for any outcome variable between class S and LL-variant of the (GT) n polymorphism. Haplotype analysis confirmed dominance of the A(-413)T SNP over the (GT) n polymorphism. In conclusion, HO-1 genotype is associated with outcome after liver transplantation. These findings suggest that HO-1 mediates graft survival after liver transplantation.

rPSGL-Ig for Improvement of Early Liver Allograft Function: A Double-Blind, Placebo-Controlled, Single-Center Phase II Study†

“…However, unlike in most animal studies, we failed to validate HO-1 as a biomarker of hepatic IRI. HO-1 promoter studies based on (GT)m microsatellite polymorphisms suggest that stronger HO-1 expression protects from organ IRI, and conversely, polymorphisms correlating with lower HO-1 response worsen the pathology (29). Hence, more analyses are needed to precisely attribute a cytoprotective action to HO-1 in transplant patients.…”

A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation

“…The liver enzyme-based determination of IR injury is arbitrary and several definitions have been used [4,19,20,23]. We correlated the donor or recipient TLR4 D299G with respect to a more stringently defined outcome, initial good graft function (IGGF; see Method section Table 3).…”

Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury

“…Hepatic ischemia and IR are the leading causes of clinical liver damage and occur [5] during major trauma concomitant with blood loss, extensive liver resection during tumor removal and liver transplantation [37] . Steatosis is a major risk factor for liver surgery because steatotic livers respond poorly to IRI.…”

“…A wide variety of chemopreventive agents that elicit cytoprotective, anti-inflammatory and/or antioxidant effects by the induction of HO-1 expression have been recognized [58] . While continuing efforts should be geared towards the search for novel hepatoprotective [59] agents targeting HO-1, certain synthetic or naturally occurring substances already identified appear to induce HO-1 expression as part of their chemoprevention/chemoprotective effects against hepatocarcinogenesis [37] and should be further investigated.…”