title: Cyclosporine and methotrexate-related pharmacogenomic predictors of acute graft-versus-host disease.
abstract: Effective immunosuppression is mandatory to prevent graft-versus-host disease and to achieve a successful clinical outcome of hematopoietic stem cell transplantation. Here we tested whether germline single nucleotide polymorphisms in 20 candidate genes related to methotrexate and cyclosporine metabolism and activity influence the incidence of graft-versus-host disease in patients who undergo stem cell transplantation for hematologic disorders. Recipient genetic status of the adenosine triphosphate-binding cassette sub-family C1 and adenosine triphosphate-binding cassette sub-family C2 transporters, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/ inosine monophosphate cyclohydrolase within the methotrexate pathway, and nuclear factor of activated T cells (cytoplasmic 1) loci exhibit a remarkable influence on severe acute graft-versus-host disease prevalence. Indeed, an increased risk of acute graft-versus-host disease was observed in association with single nucleotide polymorphisms located in 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (hazard ratio=3.04; P=0.002), nuclear factor of activated T cells (cytoplasmic 1) (hazard ratio=2.69; P=0.004), adenosine triphosphate-binding cassette sub-family C2 (hazard ratio=3.53; P=0.0018) and adenosine triphosphate-binding cassette sub-family C1 (hazard ratio=3.67; P=0.0005). While donor single nucleotide polymorphisms of dihydrofolate reductase and solute carrier family 19 (member 1) genes are associated with a reduced risk of acute graft-versus-host disease (hazard ratio=0.32-0.41; P=0.0009-0.008), those of nuclear factor of activated T cells (cytoplasmic 2) are found to increase such risk (hazard ratio=3.85; P=0.0004). None of the tested single nucleotide polymorphisms was associated with the occurrence of chronic graft-versus-host disease. In conclusion, by targeting drug-related biologically relevant genes, this work emphasizes the potential role of germline biomarkers in predicting acute graft-versus-host disease. Further investigations are warranted to improve our understanding of these relationships to personalize immunosuppressive therapy and optimize outcomes.
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier de l'Université Laval (CHU de Québec) Research Center, Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Laverdière
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier de l'Université Laval (CHU de Québec) Research Center, Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
authors.affiliation: INSERM UMRS 940, Institut Universitaire d'Hématologie, Université Paris-Diderot and Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint Louis, CIB-HOG, AP-HP, Paris, France.
authors.forename: Ryad
authors.initials: R
authors.lastname: Tamouza
authors.affiliation: INSERM UMRS 940, Institut Universitaire d'Hématologie, Université Paris-Diderot and Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint Louis, CIB-HOG, AP-HP, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Loiseau
authors.affiliation: Inserm UMRS 940, Institut Universitaire d'Hématologie, Université Paris-Diderot and Service d'Hématologie-Greffe de Moelle, Hôpital Saint-Louis, AP-HP, Paris, France.
authors.forename: Regis
authors.initials: R
authors.lastname: Peffault de Latour
authors.affiliation: Inserm UMRS 940, Institut Universitaire d'Hématologie, Université Paris-Diderot and Service d'Hématologie-Greffe de Moelle, Hôpital Saint-Louis, AP-HP, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Robin
authors.affiliation: CHU de Québec Research Center; Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Félix
authors.initials: F
authors.lastname: Couture
authors.affiliation: CHU de Québec Research Center; Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Filion
authors.affiliation: CHU de Québec Research Center; Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Lalancette
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier de l'Université Laval (CHU de Québec) Research Center, Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Tourancheau
authors.affiliation: INSERM UMRS 940, Institut Universitaire d'Hématologie, Université Paris-Diderot and Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint Louis, CIB-HOG, AP-HP, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.affiliation: Inserm UMRS 940, Institut Universitaire d'Hématologie, Université Paris-Diderot and Service d'Hématologie-Greffe de Moelle, Hôpital Saint-Louis, AP-HP, Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.affiliation: CHU de Québec Research Center; Faculty of Medicine, Laval University, Québec, Canada eric.levesque@crchuq.ulaval.ca gerard.socie@paris7.jussieu.fr.
authors.forename: Éric
authors.initials: É
authors.lastname: Lévesque
mesh_terms: D000208:Acute Disease; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D002908:Chronic Disease; D015331:Cohort Studies; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D019337:Hematologic Neoplasms / Q000150:complications / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015994:Incidence; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D008727:Methotrexate