title: 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.
authors: Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa, Japan.
authors: Luis J
authors: LJ
authors: Espinoza
authors: Akiyoshi
authors: A
authors: Takami
authors: Katsuya
authors: K
authors: Nakata
authors: Kayoko
authors: K
authors: Yamada
authors: Makoto
authors: M
authors: Onizuka
authors: Takakazu
authors: T
authors: Kawase
authors: Hiroshi
authors: H
authors: Sao
authors: Hideki
authors: H
authors: Akiyama
authors: Koichi
authors: K
authors: Miyamura
authors: Shinichiro
authors: S
authors: Okamoto
authors: Masami
authors: M
authors: Inoue
authors: Takahiro
authors: T
authors: Fukuda
authors: Yasuo
authors: Y
authors: Morishima
authors: Yoshihisa
authors: Y
authors: Kodera
authors: Shinji
authors: S
authors: Nakao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000401:mortality*; D002648:Child; D002675:Child, Preschool; D014644:Genetic Variation; D005838:Genotype; D053804:Granzymes / Q000235:genetics*; D006680:HLA Antigens / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000401:mortality / Q000628:therapy; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009026:Mortality; D009196:Myeloproliferative Disorders / Q000401:mortality / Q000628:therapy*; D011110:Polymorphism, Genetic; D011379:Prognosis; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D006680:HLA Antigens; D053804:Granzymes