A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation

Haruka Nomoto, Akiyoshi Takami, J. Luis Espinoza, Keitaro Matsuo, Shohei Mizuno, Makoto Onizuka, Koichi Kashiwase, Yasuo Morishima, Takahiro Fukuda, Yoshihisa Kodera, Noriko Doki, Koichi Miyamura, Takehiko Mori, Shinji Nakao, Shigeki Ohtake, Eriko Morishita

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Thrombomodulin, encoded by the THBD gene, is a critical regulator of coagulation and innate immunity. Its gene variant (rs3176123, 2729A>C) in the 3′ untranslated region has been reported to be associated with vasculopathies. The present study analyzed the impact of THBD variation on transplant outcomes in a cohort of 317 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor A/C or C/C genotype vs. the donor A/A genotype resulted in a lower incidence of grades II–IV acute graft-versus-host disease [GVHD; hazard ratio (HR) 0.66; 95 % confidence interval (CI) 0.44–0.99; P = 0.05] according to a multivariate analysis. In patients with grades II–IV acute GVHD, the donor A/C or C/C genotype vs. the donor A/A genotype was associated with significantly better overall survival rates (HR 0.45; 95 % CI 0.21–0.99, P = 0.05), while this effect was absent in other patients. A functional analysis using lymphocytes obtained from healthy individuals revealed that the 2729C allele has a higher level of THBD mRNA than the 2729A allele. These findings suggest the functional relevance of the rs3176123 variation and indicate that higher thrombomodulin expression by individuals with the 2729C allele likely accounts for their decreased risk for acute GVHD development and subsequent mortality.

Original languageEnglish
Pages (from-to)460-470
Number of pages11
JournalInternational Journal of Hematology
Volume102
Issue number4
DOIs
Publication statusPublished - 2015 Oct 1

Fingerprint

Thrombomodulin
Graft vs Host Disease
Bone Marrow Transplantation
Tissue Donors
Genotype
Mortality
Genes
Alleles
Confidence Intervals
3' Untranslated Regions
Hematologic Neoplasms
Innate Immunity
Japan
Multivariate Analysis
Survival Rate
Bone Marrow
Lymphocytes
Transplants
Messenger RNA
Incidence

Keywords

  • Bone marrow transplantation
  • Graft-versus-host disease
  • Single nucleotide variation
  • THBD
  • Unrelated donor

ASJC Scopus subject areas

  • Hematology

Cite this

A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation. / Nomoto, Haruka; Takami, Akiyoshi; Espinoza, J. Luis; Matsuo, Keitaro; Mizuno, Shohei; Onizuka, Makoto; Kashiwase, Koichi; Morishima, Yasuo; Fukuda, Takahiro; Kodera, Yoshihisa; Doki, Noriko; Miyamura, Koichi; Mori, Takehiko; Nakao, Shinji; Ohtake, Shigeki; Morishita, Eriko.

In: International Journal of Hematology, Vol. 102, No. 4, 01.10.2015, p. 460-470.

Research output: Contribution to journalArticle

Nomoto, H, Takami, A, Espinoza, JL, Matsuo, K, Mizuno, S, Onizuka, M, Kashiwase, K, Morishima, Y, Fukuda, T, Kodera, Y, Doki, N, Miyamura, K, Mori, T, Nakao, S, Ohtake, S & Morishita, E 2015, 'A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation', International Journal of Hematology, vol. 102, no. 4, pp. 460-470. https://doi.org/10.1007/s12185-015-1852-7
Nomoto, Haruka ; Takami, Akiyoshi ; Espinoza, J. Luis ; Matsuo, Keitaro ; Mizuno, Shohei ; Onizuka, Makoto ; Kashiwase, Koichi ; Morishima, Yasuo ; Fukuda, Takahiro ; Kodera, Yoshihisa ; Doki, Noriko ; Miyamura, Koichi ; Mori, Takehiko ; Nakao, Shinji ; Ohtake, Shigeki ; Morishita, Eriko. / A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation. In: International Journal of Hematology. 2015 ; Vol. 102, No. 4. pp. 460-470.
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abstract = "Thrombomodulin, encoded by the THBD gene, is a critical regulator of coagulation and innate immunity. Its gene variant (rs3176123, 2729A>C) in the 3′ untranslated region has been reported to be associated with vasculopathies. The present study analyzed the impact of THBD variation on transplant outcomes in a cohort of 317 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor A/C or C/C genotype vs. the donor A/A genotype resulted in a lower incidence of grades II–IV acute graft-versus-host disease [GVHD; hazard ratio (HR) 0.66; 95 {\%} confidence interval (CI) 0.44–0.99; P = 0.05] according to a multivariate analysis. In patients with grades II–IV acute GVHD, the donor A/C or C/C genotype vs. the donor A/A genotype was associated with significantly better overall survival rates (HR 0.45; 95 {\%} CI 0.21–0.99, P = 0.05), while this effect was absent in other patients. A functional analysis using lymphocytes obtained from healthy individuals revealed that the 2729C allele has a higher level of THBD mRNA than the 2729A allele. These findings suggest the functional relevance of the rs3176123 variation and indicate that higher thrombomodulin expression by individuals with the 2729C allele likely accounts for their decreased risk for acute GVHD development and subsequent mortality.",
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AU - Nomoto, Haruka

AU - Takami, Akiyoshi

AU - Espinoza, J. Luis

AU - Matsuo, Keitaro

AU - Mizuno, Shohei

AU - Onizuka, Makoto

AU - Kashiwase, Koichi

AU - Morishima, Yasuo

AU - Fukuda, Takahiro

AU - Kodera, Yoshihisa

AU - Doki, Noriko

AU - Miyamura, Koichi

AU - Mori, Takehiko

AU - Nakao, Shinji

AU - Ohtake, Shigeki

AU - Morishita, Eriko

PY - 2015/10/1

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N2 - Thrombomodulin, encoded by the THBD gene, is a critical regulator of coagulation and innate immunity. Its gene variant (rs3176123, 2729A>C) in the 3′ untranslated region has been reported to be associated with vasculopathies. The present study analyzed the impact of THBD variation on transplant outcomes in a cohort of 317 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor A/C or C/C genotype vs. the donor A/A genotype resulted in a lower incidence of grades II–IV acute graft-versus-host disease [GVHD; hazard ratio (HR) 0.66; 95 % confidence interval (CI) 0.44–0.99; P = 0.05] according to a multivariate analysis. In patients with grades II–IV acute GVHD, the donor A/C or C/C genotype vs. the donor A/A genotype was associated with significantly better overall survival rates (HR 0.45; 95 % CI 0.21–0.99, P = 0.05), while this effect was absent in other patients. A functional analysis using lymphocytes obtained from healthy individuals revealed that the 2729C allele has a higher level of THBD mRNA than the 2729A allele. These findings suggest the functional relevance of the rs3176123 variation and indicate that higher thrombomodulin expression by individuals with the 2729C allele likely accounts for their decreased risk for acute GVHD development and subsequent mortality.

AB - Thrombomodulin, encoded by the THBD gene, is a critical regulator of coagulation and innate immunity. Its gene variant (rs3176123, 2729A>C) in the 3′ untranslated region has been reported to be associated with vasculopathies. The present study analyzed the impact of THBD variation on transplant outcomes in a cohort of 317 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor A/C or C/C genotype vs. the donor A/A genotype resulted in a lower incidence of grades II–IV acute graft-versus-host disease [GVHD; hazard ratio (HR) 0.66; 95 % confidence interval (CI) 0.44–0.99; P = 0.05] according to a multivariate analysis. In patients with grades II–IV acute GVHD, the donor A/C or C/C genotype vs. the donor A/A genotype was associated with significantly better overall survival rates (HR 0.45; 95 % CI 0.21–0.99, P = 0.05), while this effect was absent in other patients. A functional analysis using lymphocytes obtained from healthy individuals revealed that the 2729C allele has a higher level of THBD mRNA than the 2729A allele. These findings suggest the functional relevance of the rs3176123 variation and indicate that higher thrombomodulin expression by individuals with the 2729C allele likely accounts for their decreased risk for acute GVHD development and subsequent mortality.

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