title: The impact of thiopurine-S-methyltransferase genotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases.
abstract: OBJECTIVE
  The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of inflammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA.
  
  
  METHODS
  The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status.
  
  
  RESULTS
  Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no significant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed.
  
  
  CONCLUSIONS
  The incidence of leukopenia in TPMT mutant patients was significantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).
authors.affiliation: Department of Internal Medicine V, Division of Gastroenterology and Hepatology, University Hospital Bratislava Ruzinov, Slovakia. tibor.hlavaty2@gmail.com
authors.forename: T
authors.initials: T
authors.lastname: Hlavaty
authors.forename: M
authors.initials: M
authors.lastname: Batovsky
authors.forename: D
authors.initials: D
authors.lastname: Balakova
authors.forename: I
authors.initials: I
authors.lastname: Pav
authors.forename: P
authors.initials: P
authors.lastname: Celec
authors.forename: M
authors.initials: M
authors.lastname: Gregus
authors.forename: M
authors.initials: M
authors.lastname: Zakuciova
authors.forename: M
authors.initials: M
authors.lastname: Hlista
authors.forename: M
authors.initials: M
authors.lastname: Horakova
authors.forename: B
authors.initials: B
authors.lastname: Desatova
authors.forename: T
authors.initials: T
authors.lastname: Koller
authors.forename: J
authors.initials: J
authors.lastname: Toth
authors.forename: L
authors.initials: L
authors.lastname: Kadasi
authors.forename: M
authors.initials: M
authors.lastname: Huorka
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine