title: TPMT and ITPA genetic variants in Lithuanian inflammatory bowel disease patients: Prevalence and azathioprine-related side effects.
abstract: OBJECTIVE
  Inter-individual thiopurine metabolism variability can influence treatment outcomes in inflammatory bowel disease (IBD) patients. Genetic polymorphisms in thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) were linked with toxicity of azathioprine (AZA). The aim of the study was to investigate frequencies of TPMT and ITPA polymorphisms in Lithuanian IBD patients and analyze their association with AZA-related adverse events.
  
  
  METHODS
  Polymorphisms in TPMT (TPMT*2,*3B,*3C,*3A) and ITPA (rs1127354, rs7270101) genes were determined using PCR-RFLP and TaqMan(®) genotyping assays. 551 consecutive Lithuanian IBD patients were genotyped. The use of AZA and its side effects were assessed retrospectively according to hospital medical records.
  
  
  RESULTS
  Frequencies of TPMT*3A, TPMT*3B and TPMT*3C alleles were 3.1%, 0.5% and 0.1%, respectively. TPMT*2 genetic variant was not detected in the study group. The distribution of minor alleles for ITPA rs1127354 and rs7270101 polymorphisms was 9.9% and 10.5%, respectively. AZA was prescribed in 82 patients and it provoked myelotoxicity in 11%, hepatotoxicity in 6.1%, dyspepsia in 6.1%, and pancreatitis in 3.6% of cases. Among patients who had AZA-related myelotoxicity, 11.1% were TPMT compound heterozygous, 44.4% had heterozygous genotype (P<0.01). Frequencies of ITPA minor alleles were similar among the patients with and without AZA-related side effects.
  
  
  CONCLUSIONS
  Frequencies of TPMT and ITPA variant alleles in Lithuanian IBD group were similar to those observed in the Northern-Eastern Europe Caucasian populations. Polymorphisms in TPMT might be associated with myelotoxicity and leukopenia in AZA treated patients, while ITPA variant alleles appear not to be linked with treatment-related side effects.
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Ruta
authors.initials: R
authors.lastname: Steponaitiene
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Juozas
authors.initials: J
authors.lastname: Kupcinskas
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Santa
authors.initials: S
authors.lastname: Survilaite
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Greta
authors.initials: G
authors.lastname: Varkalaite
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Laimas
authors.initials: L
authors.lastname: Jonaitis
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Gediminas
authors.initials: G
authors.lastname: Kiudelis
authors.affiliation: Clinic of Gastroenterology, Nephrourology and Surgery, Medical Faculty of Vilnius University, Vilnius University, Vilnius, Lithuania.
authors.forename: Goda
authors.initials: G
authors.lastname: Denapiene
authors.affiliation: Clinic of Gastroenterology, Nephrourology and Surgery, Medical Faculty of Vilnius University, Vilnius University, Vilnius, Lithuania.
authors.forename: Jonas
authors.initials: J
authors.lastname: Valantinas
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Jurgita
authors.initials: J
authors.lastname: Skieceviciene
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. Electronic address: l.kupcinskas@gmail.com.
authors.forename: Limas
authors.initials: L
authors.lastname: Kupcinskas
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D008097:Lithuania / Q000453:epidemiology; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase
keywords: Azathioprine; IBD; ITPA; Polymorphism; TPMT