Mary Diviney

Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate

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.

The Effect of Folinic Acid on Methylenetetrahydrofolate Reductase Polymorphisms in Methotrexate-Treated Allogeneic Hematopoietic Stem Cell Transplants

This study examined the contribution single nucleotide polymorphisms (SNPs) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have on clinical outcomes in hematopoietic stem cell transplant patients treated with the antiproliferative drug methotrexate. Two common SNPs, 677C>T and 1298A>C, were genotyped by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) from samples obtained from patient DNA samples. Eleven clinical outcomes including survival and graft-versus-host disease (GVHD) were assessed against donor and recipient MTHFR genotypes against pretransplantation variables. Folinic acid (FA) as treatment for oral mucositis toxicity was used at investigator discretion in 72 of 140. Donor MTHFR 1298AA genotype was associated with decreased 5-year survival (P = .03) and event-free survival (EFS) (P = .02) in patients withheld FA. Donor MTHFR 677CC genotype was associated with earlier GVHD (P = .003), and more severe acute GVHD (P = 0.02). FA was significantly associated with decreased survival (P = 0.02) in patients given a donor MTHFR 677CT transplant. FA was significantly associated with decreased survival (P = .04), EFS (P = .009) in patients given a donor MTHFR 1298AC transplant MTHFR gene polymorphisms indicate a potentially useful gene for donor selection where more than one donor is available. Use of FA following transplantation should be reconsidered in the context of patient and donor MTHFR genotypes.

Nomenclature and Serology of HLA Class I and Class II Alleles

This overview presents nomenclature and serology information on human leucocyte antigens, or HLA molecules, which are encoded by a cluster of genes linked on the short arm of chromosome 6. This region is known as the major histocompatibility coclass II molecules based upon their structure, tissue distribution, and source of peptide antigen, as well as upon their interactions with T cell subsets.

HLA and drug hypersensitivity

Approximately 7% of individuals suffer from adverse drug reactions (ADR) some of which are life threatening. While ADRs can manifest in a variety of ways, approximately one-third are associated with hypersensitivity reactions (HR). The genomic era has created the means of elucidating the gene(s) involved in specific drug responses and permitting tailoring of individual drug therapy. Molecular typing has revealed three examples where HLA genes play a central role in the immune response to drug therapy. The outstanding example is the association of HLA-B*5701 in patients with a HR to the nucleoside analog reverse transcriptase inhibitor (NRTI) abacavir, which is used in the treatment of HIV positive and AIDS patients. The strong association with B*5701 necessitates HLA gene typing prior to treatment, with HLA-B*5701 positive patients being offered alternative therapy. The Royal College of Pathologists of Australasia (RCPA) in conjunction with the Australian and South East Asian Tissue Typing Association is currently running a quality assurance program to monitor laboratories performing this test. Other examples include the strong association of Stevens– Johnson syndrome and toxic epidermal necrosis (TEN) with HLA-B*1502, and treatment with the anti-convulsant drug carbamezepine in Han Chinese, Thais and Malays, and HLA-B*5801 with the use of allopurinol for the treatment of hyperuricemia.