Toll-like receptor genetic variations in bone marrow transplantation.

Kaori Uchino,Koichi Kashiwase,Makoto Onizuka,Yasuhito Nannya,Shohei Mizuno,Aiko Sato-Otsubo,Koichi Miyamura,Akiyoshi Takami,Takehiko Mori,Yasuo Morishima,Tomohiro Horio,Yoshihisa Kodera,Takahiro Fukuda,J Luis Espinoza,Ichiro Hanamura,Motonori Mizutani,Noriko Doki,Seishi Ogawa

doi:10.18632/oncotarget.17315

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.

Highlights

Allogeneic hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for hematologic malignancies [1]
We retrospectively examined whether or not genetic variations in toll-like receptor 1, toll-like receptor 2, and toll-like receptor 4 affected transplant outcomes in a cohort of 365 patients who underwent unrelated HLA-matched bone marrow transplantation
The rs5743551 (-7202G>A) variation in the TLR1 gene, the rs7656411 (22215G>T) variation in the TLR2 gene and the rs11536889 (+3725G>C) variation in the TLR4 gene were genotyped in 365 recipients with hematologic malignancies and their unrelated donors in the discovery cohort (Table 1)

Summary

Introduction

Allogeneic hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for hematologic malignancies [1]. 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.

Results

Conclusion