title: Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate.
abstract: Methotrexate (MTX), used as a graft-versus-host disease (GvHD) prophylactic agent in hematopoietic stem cell transplantation (HSCT), exerts its effect via folate cycle inhibition. A critical enzyme involved in folate metabolism is 5,10-methylenetetrahydrofolate reductase (MTHFR). We examined the association of a single nucleotide polymorphism (SNP) at position 677 in the MTHFR gene on GvHD outcomes in allogeneic HSCT patients administered MTX. MTHFR genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 193 HSCT patients and donors. A total of 140 patients were transplanted with an HLA-matched related donor and 53 with an unrelated donor. GvHD outcomes were compared between genotypes by univariate and multivariate analysis. The combined donor 677CT and TT genotypes were associated with a decreased incidence of GvHD (acute and chronic combined) in HSCT recipients with an HLA-matched related donor (75% at 1 year in the CT and TT group compared with 91% in the wild type CC group, P=0.01), increased time to onset of first GvHD (P=0.001) and time to first GvHD treated with systemic therapy (P=0.022). Unrelated donor MTHFR genotype was not associated with outcome parameters and no associations of recipient genotype in either related or unrelated donor cohorts were observed.
authors.affiliation: Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Murphy
authors.forename: M
authors.initials: M
authors.lastname: Diviney
authors.forename: J
authors.initials: J
authors.lastname: Szer
authors.forename: P
authors.initials: P
authors.lastname: Bardy
authors.forename: A
authors.initials: A
authors.lastname: Grigg
authors.forename: R
authors.initials: R
authors.lastname: Hoyt
authors.forename: B
authors.initials: B
authors.lastname: King
authors.forename: L
authors.initials: L
authors.lastname: Macgregor
authors.forename: R
authors.initials: R
authors.lastname: Holdsworth
authors.forename: J
authors.initials: J
authors.lastname: McCluskey
authors.forename: B D
authors.initials: BD
authors.lastname: Tait
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004247:DNA / Q000737:chemistry; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005838:Genotype; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D004247:DNA; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate