Genetic Variants of Human Granzyme B Predict Transplant Outcomes after HLA Matched Unrelated Bone Marrow Transplantation for Myeloid Malignancies

Abstract

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41–0.89; P = 0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27–0.86, P = 0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47–0.99; P = 0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35–1.06; P = 0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT.

Genetic variations in T-cell activation and effector pathways modulate alloimmune responses after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies

“…Espinoza et al reported that donors and/or patients with the granzyme B +55 G-allele positive genotype were associated with improved overall survival after unrelated HLA-fully matched T-cell-replete bone marrow transplantation, but failed to find any significant association with aGVHD. 45 We identified for the first time that polymorphism of granzyme B +55 influenced the risk of aGVHD and that the AA genotype was a strong candidate for the susceptibility genotype. The non-synonymous single nucleotide polymorphism +55 A/G, located in exon 2, is responsible for the amino acid substitution of a glutamine (CAA) to arginine (CGA) (numbering with reference to the human chymotrypsinogen A sequence).…”

Controversies in granzyme biology

“…In one study, the QPY allele was linked with higher incidence of Epstein Barr virus‐associated hemophagocytic lymphohistiocytosis ; on the other hand, no link was found between Grz B polymorphisms and incidence of familial hemophagocytic lymphohistiocytosis . Recently, specific Grz B genotypes have also been linked to breast cancer incidence and bone marrow transplantation outcomes after myeloid malignancies . The significance of these findings and any relationship with Grz B biology per se remains an open question.…”

Toll-like receptor 1 variation increases the risk of transplant-related mortality in hematologic malignancies

“…Underlined and bold results represent P b 0.05. To the best of our knowledge, this is the first report identifying the same genotype of a single nucleotide variation in both the recipients and donors as having similar impacts on transplant outcomes among single nucleotide variations previously known to be significant [25][26][27][28][29][30]. This could result from the inherent nature of TLR1, which is ubiquitously expressed in various tissues such as white blood cells, lymph nodes, endothelium, lung, gut, skin, and liver, and plays critical roles in antimicrobial immunity [1,2].…”