Influence of Polymorphism within the Heme Oxygenase-I Promoter on Overall Survival and Transplantation-Related Mortality after Allogeneic Stem Cell Transplantation

Abstract

Aside from major and minor histocompatibility antigens, genetic polymorphisms of various donor and host genes have been found to be risk factors for graft-versus-host disease and transplantation-related mortality (TRM). The heme oxygenase I (HO-I) protein has been implicated in regulating inflammatory response and has been described as a "protective gene" in solid organ transplantation. In humans, the promoter region displays length polymorphism due to a variable number of GT repeats. Individuals exhibiting 29 or fewer GT repeats express higher levels of HO-I on cellular stress compared with individuals with 30 or more GT repeats. We retrospectively analyzed length polymorphisms of 92 donor-host pairs undergoing allogeneic stem cell transplantation. Our findings demonstrate that mainly donor polymorphism leading to high expression of HO-1 (<30 GT repeats) on stress signals is associated with reduced overall survival, and that TRM is significantly increased in this group. This reduction in survival was most prominent when unrelated donors were used. Polymorphisms of the recipient HO-1 genes did not influence posttransplantation outcomes. We conclude that HO-1 polymorphism represents a new genetic risk factor for TRM and overall survival.

(GT)n Repeat Polymorphism in Heme Oxygenase-1 (HO-1) Correlates with Clinical Outcome after Myeloablative or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

“…In a cohort of 92 patients transplanted with in vivo T-cell depleted grafts from matched related donors MA-HCT, Gerbitz et al observed that donors with high HO-1 expression (based on (GT) n repeat genotype) and thus increased anti-inflammatory drive, were associated with inferior survival due to grade III-IV acute GVHD≥3 [15]. Gerbitz et al hypothesize that expression of HO-1 above a certain threshold may lead to an excessive oxidative burst that induces tissue damage [16].…”

NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies

“…Polymorphisms in genes encoding for nucleotide-binding oligomerization domain 2 (NOD2)/caspase recruitment domain 15 (CARD15), 9 heme oxygenase-1 (HO-1) promoter, 6 nase citullinating enzymes 4 (PADI4) 13 and methylenetetrahydrofolate reductase (MTHFR) 14 have been shown to influence the outcome after allogeneic SCT. Most of them are associated with the development of GVHD.…”

“…3 Previous investigations have revealed that several single nucleotide polymorphisms (SNP) which affect individual immune response to infections and inflammatory reactions are associated with the risk of GVHD and transplant outcomes. [4][5][6][7][8][9][10][11][12][13][14][15] NKG2D is an activating and co-stimulatory receptor belonging to the C-type lectin-like family of transmembrane proteins and is expressed as a homodimer on natural killer (NK) cells, CD8…”

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

“…2 Previous investigations have revealed that several single-nucleotide polymorphisms (SNPs), which impact on individual immune response to infections and inflammatory reactions are associated with SCT outcomes including the risk of acute GVHD. [3][4][5][6][7][8][9][10][11][12] IL-17, also known as IL-17A, is the hallmark cytokine of a new T-helper subset termed Th17. [13][14][15][16] gdT cells, macrophages and neutrophils are sources of IL-17 as well.…”