TY - JOUR
T1 - A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation
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
N1 - Publisher Copyright:
© 2015, The Japanese Society of Hematology.
PY - 2015/10/1
Y1 - 2015/10/1
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.
KW - Bone marrow transplantation
KW - Graft-versus-host disease
KW - Single nucleotide variation
KW - THBD
KW - Unrelated donor
UR - http://www.scopus.com/inward/record.url?scp=84951567231&partnerID=8YFLogxK
U2 - 10.1007/s12185-015-1852-7
DO - 10.1007/s12185-015-1852-7
M3 - Article
C2 - 26246110
AN - SCOPUS:84951567231
SN - 0925-5710
VL - 102
SP - 460
EP - 470
JO - International Journal of Hematology
JF - International Journal of Hematology
IS - 4
ER -