title: Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprine-induced myelosuppression in heart transplant recipients.
abstract: Azathioprine (AZA) is metabolized via the cytosolic enzyme thiopurine S-methyltransferase (TPMT). TPMT activity exhibits genetic polymorphism with four prevalent (75%) mutant alleles TPMT*2 (G238C) and TPMT*3 (A719G and/or G460A) and a wild-type allele TPMT*1. To test the hypothesis that presence of these mutations is associated with greater toxicity of AZA in heart transplant recipients, 30 consecutive patients treated with AZA were followed up for the first month after heart transplant. Mutation of TPMT gene (mutation-specific polymerase chain reaction-based methods) was observed in four patients (A719G: n = 2; A719G plus G460: n = 2). Agranulocytosis did not occur in patients with the wild genotype. It occurred in the two patients with mutation A719G and there was a 40% drop in neutrophils in the two other patients. Discontinuation of AZA in the four mutant patients corrected for the drop. Presence of TPMT mutations is associated with a greater likelihood of agranulocytosis. Determination of these mutations could reduce the risk for hematological side-effects.
authors.affiliation: Hôpital Cardiologique, Lyon, France.
authors.forename: L
authors.initials: L
authors.lastname: Sebbag
authors.forename: P
authors.initials: P
authors.lastname: Boucher
authors.forename: P
authors.initials: P
authors.lastname: Davelu
authors.forename: P
authors.initials: P
authors.lastname: Boissonnat
authors.forename: G
authors.initials: G
authors.lastname: Champsaur
authors.forename: J
authors.initials: J
authors.lastname: Ninet
authors.forename: G
authors.initials: G
authors.lastname: Dureau
authors.forename: J F
authors.initials: JF
authors.lastname: Obadia
authors.forename: J J
authors.initials: JJ
authors.lastname: Vallon
authors.forename: J
authors.initials: J
authors.lastname: Delaye
mesh_terms: D000328:Adult; D000380:Agranulocytosis / Q000139:chemically induced; D001379:Azathioprine / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005544:Forecasting; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012189:Retrospective Studies
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine