Decreased risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with the 5,10-methylenetetrahydrofolate reductase 677TT genotype.
Polymorphism in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, has been shown to affect the sensitivity of patients to folate-based drugs such as methotrexate. In this study, we investigated whether a common single nucleotide polymorphism at position 677 in the donor or recipient's MTHFR gene affects the risk for acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling donors when the recipient receives prophylactic treatment with methotrexate for GVHD. MTHFR genotypes were determined in 159 recipients with a hematological disease and their donors using polymerase chain reaction-restriction fragment length polymorphism analysis of genomic DNA. The 677TT genotype, which encodes an enzyme with approximately 30% of the activity of the wild-type (677CC), was observed in 13% of patients and in 8% of normal donors. Multivariate analyses demonstrated a significant association between 677TT genotype in patients and a lower incidence of grade I-IV acute GVHD (relative risk, 0.35; 95% confidence interval, 0.13-0.95; P = 0.040). There was no association between the incidence of acute GVHD and the donor MTHFR genotypes. These results suggest that greater immunosuppression by methotrexate due to low MTHFR enzyme activity decreases the risk of acute GVHD in recipients of allogeneic HSCT.
Sugimoto
Kyoko
K
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
Murata
Makoto
M
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan. mmurata@med.nagoya-u.ac.jp.
Onizuka
Makoto
M
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.|Department of Hematology and Rheumatology, Tokai University School of Medicine, Bouseidai, Japan.
Inamoto
Yoshihiro
Y
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
Terakura
Seitaro
S
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
Kuwatsuka
Yachiyo
Y
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
Oba
Taku
T
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
Miyamura
Koichi
K
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
Kodera
Yoshihisa
Y
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
Naoe
Tomoki
T
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D006402:Hematologic Diseases / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D019520:Living Donors; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate