Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies

Luis J. Espinoza, Akiyoshi Takami, Katsuya Nakata, Kayoko Yamada, Makoto Onizuka, Takakazu Kawase, Hiroshi Sao, Hideki Akiyama, Koichi Miyamura, Shinichiro Okamoto, Masami Inoue, Takahiro Fukuda, Yasuo Morishima, Yoshihisa Kodera, Shinji Nakao

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere23827
JournalPLoS One
Volume6
Issue number8
DOIs
Publication statusPublished - 2011 Aug 23

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Transplantation (surgical)
Granzymes
bone marrow transplant
Transplants
Medical Genetics
Bone Marrow Transplantation
confidence interval
Bone
genotype
Hazards
genetic polymorphism
Polymorphism
Genotype
Confidence Intervals
Neoplasms
graft rejection
myeloid leukemia
autoimmunity
serine proteinases
lymphoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies. / Espinoza, Luis J.; Takami, Akiyoshi; Nakata, Katsuya; Yamada, Kayoko; Onizuka, Makoto; Kawase, Takakazu; Sao, Hiroshi; Akiyama, Hideki; Miyamura, Koichi; Okamoto, Shinichiro; Inoue, Masami; Fukuda, Takahiro; Morishima, Yasuo; Kodera, Yoshihisa; Nakao, Shinji.

In: PLoS One, Vol. 6, No. 8, e23827, 23.08.2011.

Research output: Contribution to journalArticle

Espinoza, LJ, Takami, A, Nakata, K, Yamada, K, Onizuka, M, Kawase, T, Sao, H, Akiyama, H, Miyamura, K, Okamoto, S, Inoue, M, Fukuda, T, Morishima, Y, Kodera, Y & Nakao, S 2011, 'Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies', PLoS One, vol. 6, no. 8, e23827. https://doi.org/10.1371/journal.pone.0023827
Espinoza, Luis J. ; Takami, Akiyoshi ; Nakata, Katsuya ; Yamada, Kayoko ; Onizuka, Makoto ; Kawase, Takakazu ; Sao, Hiroshi ; Akiyama, Hideki ; Miyamura, Koichi ; Okamoto, Shinichiro ; Inoue, Masami ; Fukuda, Takahiro ; Morishima, Yasuo ; Kodera, Yoshihisa ; Nakao, Shinji. / Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies. In: PLoS One. 2011 ; Vol. 6, No. 8.
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