title: TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation.
abstract: OBJECTIVE
  Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose because of higher active metabolite levels and risk of adverse events. However, in-vitro lymphocyte proliferation assays performed in participants with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared with wild-type (WT) individuals. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA.
  
  
  METHODS
  We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored by routine endomyocardial biopsies.
  
  
  RESULTS
  There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared with WT (13.1±2.8 vs. 21±4.5 U/ml red blood cell, P<0.001). Despite similar AZA dose, HZ developed severe rejection earlier (P<0.001), and the total rejection score was higher (P=0.02) than WT. AZA was discontinued more frequently in HZ (P=0.01) because of rejection. The incidence of leukopenia was similar between the groups (40 vs. 43%, P=1.0).
  
  
  CONCLUSIONS
  HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently, and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.
authors.affiliation: Department of aInternal Medicine bBiostatistics cMedicine, Division of Cardiovascular Diseases dDepartment of Molecular Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jackson J
authors.initials: JJ
authors.lastname: Liang
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Geske
authors.forename: Barry A
authors.initials: BA
authors.lastname: Boilson
authors.forename: Robert P
authors.initials: RP
authors.lastname: Frantz
authors.forename: Brooks S
authors.initials: BS
authors.lastname: Edwards
authors.forename: Sudhir S
authors.initials: SS
authors.lastname: Kushwaha
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kremers
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
authors.forename: Naveen L
authors.initials: NL
authors.lastname: Pereira
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D014644:Genetic Variation; D006084:Graft Rejection / Q000235:genetics* / Q000517:prevention & control; D016027:Heart Transplantation / Q000009:adverse effects*; D006579:Heterozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine