title: A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation.
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.
authors.affiliation: Department of Clinical Laboratory Science, Kanazawa University School of Medical Sciences, Kanazawa, Japan. haruka84@stu.kanazawa-u.ac.jp.
authors.forename: Haruka
authors.initials: H
authors.lastname: Nomoto
authors.affiliation: Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan. takami-knz@umin.ac.jp.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Takami
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. luis@staff.kanazawa-u.ac.jp.
authors.forename: J Luis
authors.initials: JL
authors.lastname: Espinoza
authors.affiliation: Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan. keitarom@med.kyushu-u.ac.jp.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Clinical Laboratory Science, Kanazawa University School of Medical Sciences, Kanazawa, Japan. shohei@aichi-med-u.ac.jp.
authors.forename: Shohei
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan. moni5@mac.com.
authors.forename: Makoto
authors.initials: M
authors.lastname: Onizuka
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan. k-kashiwase@ktks.bbc.jrc.or.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. ymorisim@aichi-cc.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.affiliation: Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo, Japan. tafukuda@ncc.go.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University, Nagoya, Japan. ykodera@river.ocn.ne.jp.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kodera
authors.affiliation: Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan. n-doki@cick.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Doki
authors.affiliation: Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan. miyamu@nagoya-1st.jrc.or.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyamura
authors.affiliation: Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. tmori@a3.keio.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Mori
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. snakao8205@staff.kanazawa-u.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Department of Clinical Laboratory Science, Kanazawa University School of Medical Sciences, Kanazawa, Japan. sohtake@staff.kanazawa-u.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ohtake
authors.affiliation: Department of Clinical Laboratory Science, Kanazawa University School of Medical Sciences, Kanazawa, Japan. eriko86@staff.kanazawa-u.ac.jp.
authors.forename: Eriko
authors.initials: E
authors.lastname: Morishita
mesh_terms: D000293:Adolescent; D000328:Adult; D064591:Allografts; D016025:Bone Transplantation; D018572:Disease-Free Survival; D005260:Female; D014644:Genetic Variation; D006086:Graft vs Host Disease / Q000235:genetics / Q000401:mortality; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000401:mortality / Q000628:therapy; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D015996:Survival Rate; D018180:Thrombomodulin / Q000235:genetics*; D019172:Transplantation Conditioning; D061349:Unrelated Donors
chemical_list: C546931:THBD protein, human; D018180:Thrombomodulin
keywords: Bone marrow transplantation; Graft-versus-host disease; Single nucleotide variation; THBD; Unrelated donor