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

作者：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

来源：International Journal of Hematology, 2015, 102(4): 460-470.

DOI：10.1007/s12185-015-1852-7

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

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.

• 出版日期2015-10