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

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An Erratum to this article was published on 09 September 2015

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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Acknowledgments

We thank all of the Japan Marrow Donor Program (JMDP) transplant teams who provided their valuable assistance in caring for the patients and donors investigated in this study. This study was supported by grants from the Ministry of Health, Labour and Welfare of Japan, the Ministry of Education, Culture, Sports and Technology of Japan (Grant Number 24591418 and 15K09513), the SENSHIN Medical Research Foundation (Osaka, Japan), the Aichi Cancer Research Foundation (Nagoya, Japan), and the 24th General Assembly of the Japanese Association of Medical Sciences (Nagoya, Japan). The funders played no role in the study design, data collection and analysis, the decision to publish or the preparation of the manuscript.

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Authors and Affiliations

  1. Department of Clinical Laboratory Science, Kanazawa University School of Medical Sciences, Kanazawa, Japan

    Haruka Nomoto, Shohei Mizuno, Shigeki Ohtake & Eriko Morishita

  2. Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan

    Akiyoshi Takami

  3. Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

    J. Luis Espinoza & Shinji Nakao

  4. Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan

    Keitaro Matsuo

  5. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan

    Makoto Onizuka

  6. Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan

    Koichi Kashiwase

  7. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

    Yasuo Morishima

  8. Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  9. Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University, Nagoya, Japan

    Yoshihisa Kodera

  10. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

    Noriko Doki

  11. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Koichi Miyamura

  12. Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

    Takehiko Mori

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  1. Haruka Nomoto
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Nomoto, H., Takami, A., Espinoza, J. et al. A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation. Int J Hematol 102, 460–470 (2015). https://doi.org/10.1007/s12185-015-1852-7

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