A Genetic Variation in the Heme Oxygenase-1 Gene Predicts the Outcome of HLA-Fully-Matched Unrelated Bone Marrow Transplantation
Authors: Morishita Eriko , Maruyama Keiko , Takami Akiyoshi , Onizuka Makoto , Kawase Takakazu , Morishima Yasuo , Fukuda Takahiro , Kodera Yoshihisa , Ohtake Shigeki , Yachie Akihiro , Nakao Shinji 
Published: October 2019

Abstract
Abstract 1976

Background:
Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in the first step of heme degradation to biliverdin, free iron, and carbon monoxide. Aside from heme degradation, HO-1 has been attributed several regulatory functions in tissue inflammation and protection against stress-induced apoptosis. Inducibility of HO-1 is moderated by a single nucleotide polymorphism (SNP) A -413 T in the promoter. It has been reported that the A-allele of this SNP is associated with higher promoter activity than T-allele. Additionally, there have been several reports on the involvement of polymorphism within the promoter region of the human HO-1 gene in various diseases of the vascular systems. Recently, the polymorphism in the HO-1 gene has been reportedly associated with the graft survival after liver transplantation. In this study we analyzed the impact of HO-1 polymorphism on transplant outcomes in patients undergoing unrelated HLA-fully-matched bone marrow transplantation (BMT) through the Japan Marrow Donation Program.

Methods and Results:
The SNP A -413 T was analyzed using the TaqMan system (Applied Biosystems). The HO-1 polymorphisms were retrospectively analyzed in a cohort of 259 pairs of patients with hematologic malignancies and their unrelated donors. The genotype frequencies of A/A, A/T and T/T were 22%, 48% and 38% in recipients and 20%, 53% and 27% in donors (P=0.41). The donor A/A or A/T genotype, a genotype expected to induce higher activity of the HO-1 gene, was associated with a better overall survival (OS) than the donor T/T genotype (55% vs. 38% @5-yr, P=0.002; Fig 1A) as well as trend toward reduced transplant-related mortality (TRM; 18% vs. 27% @5-yr, P=0.08; Fig 1B), while no significant differences between the A/A genotype and A/T genotype were noted. The beneficial effects of the donor A/A or A/T genotype were also found to be consistent on the multivariate analysis for OS (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.44 to 0.93; P=0.02) and TRM (HR, 0.59; 95% CI, 0.32 to 1.06; P=0.08). Furthermore, in the multivariate analysis the donor A/A or A/T genotype showed a tendency to a lower incidence of grades II-IV acute graft-versus-host disease (GVHD; HR, 0.68; 95% CI, 0.43 to 1.06; P=0.09). The recipient HO-1 genotypes did not significantly influence the transplant outcomes.

Conclusions:
These results suggest an association of the donor HO-1 genotype with overall survival after unrelated BMT, and may substantiate that the higher HO-1 activity by donors with the HO-1 A allele likely accounts for a reduced risk for TRM and acute GVHD in their recipients. These could therefore be useful in selecting the donor and creating therapeutic strategies for improving the final outcome of allogeneic BMT.

Disclosures:
No relevant conflicts of interest to declare.