title: The Impact of Methylenetetrahydrofolate Reductase C677T Polymorphism on Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Methotrexate Prophylaxis.
abstract: Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC), and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2) was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016). A total of 25 patients (14.1%) expired due to transplantation related mortality (TRM) during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010). This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010). The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122-2.808, P = 0.014) and non-CR state (HR = 2.841. 95% CI 1.627-4.960, P<0.001) as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX as GVHD prophylaxis.
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
authors: Ja Min
authors: http://orcid.org/0000-0003-1780-5553
authors: JM
authors: Byun
authors: Graduate School of Public Health, Seoul National University, Seoul, Korea.
authors: Hea-Lim
authors: HL
authors: Kim
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.|Cancer Research Institute, Seoul National University, Seoul, Korea.
authors: Dong-Yeop
authors: DY
authors: Shin
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.|Cancer Research Institute, Seoul National University, Seoul, Korea.
authors: Youngil
authors: Y
authors: Koh
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.|Cancer Research Institute, Seoul National University, Seoul, Korea.
authors: Sung-Soo
authors: SS
authors: Yoon
authors: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea.
authors: Moon-Woo
authors: MW
authors: Seong
authors: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea.
authors: Sung Sup
authors: SS
authors: Park
authors: Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Korea.
authors: Jin Hee
authors: JH
authors: Kim
authors: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Yun-Gyoo
authors: YG
authors: Lee
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.|Cancer Research Institute, Seoul National University, Seoul, Korea.
authors: Inho
authors: I
authors: Kim
mesh_terms: D000328:Adult; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012008:Recurrence; D015996:Survival Rate; D014184:Transplantation, Homologous
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate