title: Gene polymorphisms involved in manifestation of leucopenia, digestive intolerance, and pancreatitis in azathioprine-treated patients.
abstract: BACKGROUND
  Approximately 10-28 % of patients experience adverse drug reactions related to treatment with thiopurines. The most serious reaction is myelosuppression, typically manifested as leucopenia, which occurs in approximately 2-5 % of patients. Other adverse drug reactions that often accompany thiopurine therapy are pancreatitis, hepatotoxicity, allergic reactions, digestive intolerance, arthralgia, febrile conditions, and rash.
  
  
  OBJECTIVE
  The objective of this study was to assess the relationship between variant alleles of thiopurine S-methyltransferase (SNPs 238G > C, 460G > A and 719A > G), inosine triphosphate diphosphatase (SNPs 94C > A and IVS2 + 21A > C), and xanthine dehydrogenase (837C > T) and the occurrence of adverse drug reactions to azathioprine therapy.
  
  
  METHODS
  Genotype was determined for 188 Caucasians diagnosed with inflammatory bowel disease treated with a standard dose of azathioprine (1.4-2.0 mg/kg/day). Allelic variants were determined by PCR-REA and real-time PCR methods. Results were statistically evaluated by use of Fisher's test and by odds ratio calculation.
  
  
  RESULTS
  Variant genotype thiopurine S-methyltransferase predisposes to development of leucopenia (P = 0.003, OR = 5, CI 95 %, 1.8058-13.8444). Although not statistically significant, we observed a trend that suggested correlation between the occurrence of digestive intolerance and the variant genotype inosine triphosphate diphosphatase (P = 0.1102; OR 15.63, CI 95 %, 1.162-210.1094), and between the occurrence of pancreatitis and the variant allele xanthine dehydrogenase 837T (P = 0.1124; OR 12,1, CI 95 %, 1.15-126.37).
  
  
  CONCLUSIONS
  The variant genotype thiopurine S-methyltransferase has been associated with the occurrence of leucopenia. The involvement of polymorphisms in inosine triphosphate diphosphatase and xanthine dehydrogenase genes in the development of digestive intolerance and pancreatitis will require further verification.
authors.affiliation: Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1/3, 612 42 Brno, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Wroblova
authors.forename: Michal
authors.initials: M
authors.lastname: Kolorz
authors.forename: Marian
authors.initials: M
authors.lastname: Batovsky
authors.forename: Vladimir
authors.initials: V
authors.lastname: Zboril
authors.forename: Jana
authors.initials: J
authors.lastname: Suchankova
authors.forename: Milan
authors.initials: M
authors.lastname: Bartos
authors.forename: Boris
authors.initials: B
authors.lastname: Ulicny
authors.forename: Igor
authors.initials: I
authors.lastname: Pav
authors.forename: Ladislava
authors.initials: L
authors.lastname: Bartosova
mesh_terms: D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D000091402:Prohibitins
chemical_list: D007166:Immunosuppressive Agents; C000717331:PHB2 protein, human; D000091402:Prohibitins; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine