Decreased risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with the 5,10-methylenetetrahydrofolate reductase 677TT genotype

Abstract

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.

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

“…2 Previous investigations have revealed that several single-nucleotide polymorphisms (SNPs), which impact on individual immune response to infections and inflammatory reactions are associated with SCT outcomes including the risk of acute GVHD. [3][4][5][6][7][8][9][10][11][12] IL-17, also known as IL-17A, is the hallmark cytokine of a new T-helper subset termed Th17. [13][14][15][16] gdT cells, macrophages and neutrophils are sources of IL-17 as well.…”

Cyclosporine and methotrexate-related pharmacogenomic predictors of acute graft-versus-host disease

“…Of all methotrexate's candidate genes previously examined, MTHFR, in particular the non-synonymous C677T (rs1801133) and the A1298C (rs1801131) polymorphisms, has received great attention but yielded conflicting results. 18,23,24,[29][30][31]46 In this study, associations were found between MTHFR genetic status and grade II-IV acute GvHD; none, however, remained positive for severe acute GvHD after correction for multiple testing. Based on our data, it is suggested that the SNP associated with grade II-IV acute GvHD herein are either: (i) associated with a less severe form of the disease (grade II), and/or (ii) the lower MAF (<20%) of these variants did not allow us to demonstrate their associations with grade III-IV acute GvHD occurring at a frequency of 15% in our cohort.…”

“…[26][27][28] So far, only a few studies have addressed such an important phenotype-genotype relationship, although genetic variations in the gene coding for methylenetrahydrofolate reductase (MTHFR) enzyme have received great attention. 18,[22][23][24][29][30][31][32][33] As the inter-individual variability in GvHD occurrence among HSCT patients may be, at least partly, related to the genetic diversity of genes involved in the bioavailability and in the metabolism of methotrexate/cyclosporine A, we tested in this study whether selected single nucleotide polymorphisms (SNP) located in loci encoding molecules implicated in the methotrexate/cyclosporine A metabolic and transport pathways could influence the incidence of GvHD in HSCT recipients.…”

Genomic studies of GVHD—lessons learned thus far

“…Later studies also reported an association between recipient MTHFR SNP 677T* and a decreased risk of aGVHD. 19,46 Studies on thymidylate synthase (TS), another folate-dependent enzyme involved in DNA replication, also demonstrate the potential importance of copy number variation and its influence Genetic contributions to GVHD C Ting et al on disease progression. The TS enhancer region (TSER) is made up of 28 base pair repeats.…”