Toll-like receptor genetic variations in bone marrow transplantation

// Kaori Uchino 1 , Shohei Mizuno 1 , Aiko Sato-Otsubo 2 , Yasuhito Nannya 2 , Motonori Mizutani 1 , Tomohiro Horio 1 , Ichiro Hanamura 1 , J. Luis Espinoza 3 , Makoto Onizuka 4 , Koichi Kashiwase 5 , Yasuo Morishima 6 , Takahiro Fukuda 7 , Yoshihisa Kodera 8 , Noriko Doki 9 , Koichi Miyamura 10 , Takehiko Mori 11 , Seishi Ogawa 2 and Akiyoshi Takami 1 1 Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan 2 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 3 Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan 4 Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan 5 Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan 6 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan 7 Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo, Japan 8 Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University, Nagakute, Japan 9 Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan 10 Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan 11 Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan Correspondence to: Akiyoshi Takami, email: takami-knz@umin.ac.jp Keywords: toll-like receptor, unrelated donor, bone marrow transplantation, single nucleotide variation Received: March 15, 2017     Accepted: March 31, 2017     Published: April 21, 2017 ABSTRACT The Toll-like receptor family mediates the innate immune system through recognizing the molecular patterns of microorganisms and self-components and leading the synthesis of the inflammatory mediators. We retrospectively examined whether or not genetic variations in toll-like receptor 1 (rs5743551, -7202GQ>A), toll-like receptor 2 (rs7656411, 22215G>T), and toll-like receptor 4 (rs11536889, +3725G>C) affected transplant outcomes in a cohort of 365 patients who underwent unrelated HLA-matched bone marrow transplantation (for hematologic malignancies through the Japan Marrow Donor Program. Only donor toll-like receptor 4 variation significantly improved the survival outcomes. A multivariate analysis showed that the donor toll-like receptor 4 +3725G/G genotype was significantly associated with a better 5-year progression-free survival and a lower 5-year transplant-related mortality than other variations. Furthermore, the donor toll-like receptor 4 +3725G/G genotype was associated with a significantly lower incidence of fatal infections than other variations. The validation study of 502 patients confirmed that the donor toll-like receptor 4 +3725G/G genotype was associated with better survival outcomes. Toll-like receptor4 genotyping in transplant donors may therefore be a useful tool for optimizing donor selection and evaluating pretransplantation risks.