BACKGROUND: Inosine triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of inosine triphosphate to inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs). METHODS: Patients suffering from inflammatory bowel disease who were treated with AZA (N=160; age 43±12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2+21A>C genotypes were determined. RESULTS: AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 μmol/(gHb·h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 μmol/(gHb·h)] were frequently accompanied by leucopenias, whereas very low enzyme activities [<37.3 μmol/(gHb·h)] were associated with a higher incidence of increased liver enzymes. CONCLUSIONS: The results demonstrate a relationship between low ITPA activity and AEs and support the idea that the determination of ITPA phenotype might be an appropriate alternative to genotyping.
BACKGROUND:Inosine triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of inosine triphosphate to inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs). METHODS:Patients suffering from inflammatory bowel disease who were treated with AZA (N=160; age 43±12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2+21A>C genotypes were determined. RESULTS:AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 μmol/(gHb·h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 μmol/(gHb·h)] were frequently accompanied by leucopenias, whereas very low enzyme activities [<37.3 μmol/(gHb·h)] were associated with a higher incidence of increased liver enzymes. CONCLUSIONS: The results demonstrate a relationship between low ITPA activity and AEs and support the idea that the determination of ITPA phenotype might be an appropriate alternative to genotyping.
Authors: Peter D Simone; Lucas R Struble; Admir Kellezi; Carrie A Brown; Corinn E Grabow; Irine Khutsishvili; Luis A Marky; Youri I Pavlov; Gloria E O Borgstahl Journal: J Struct Biol Date: 2013-03-23 Impact factor: 2.867
Authors: Marcello Scala; Saskia B Wortmann; Namik Kaya; Menno D Stellingwerff; Angela Pistorio; Emma Glamuzina; Clara D van Karnebeek; Cristina Skrypnyk; Katarzyna Iwanicka-Pronicka; Dorota Piekutowska-Abramczuk; Elżbieta Ciara; Frederic Tort; Beth Sheidley; Annapurna Poduri; Parul Jayakar; Anuj Jayakar; Jariya Upadia; Nicolette Walano; Tobias B Haack; Holger Prokisch; Hesham Aldhalaan; Ehsan G Karimiani; Yilmaz Yildiz; Ahmet C Ceylan; Teresa Santiago-Sim; Amy Dameron; Hui Yang; Mehran B Toosi; Farah Ashrafzadeh; Javad Akhondian; Shima Imannezhad; Hanieh S Mirzadeh; Shazia Maqbool; Aisha Farid; Mohamed A Al-Muhaizea; Meznah O Alshwameen; Lama Aldowsari; Maysoon Alsagob; Ashwaq Alyousef; Rawan AlMass; Aljouhra AlHargan; Ali H Alwadei; Maha M AlRasheed; Dilek Colak; Hanan Alqudairy; Sameena Khan; Matthew A Lines; M Ángeles García Cazorla; Antonia Ribes; Eva Morava; Farah Bibi; Shahzad Haider; Matteo P Ferla; Jenny C Taylor; Hessa S Alsaif; Abdulwahab Firdous; Mais Hashem; Chingiz Shashkin; Kairgali Koneev; Rauan Kaiyrzhanov; Stephanie Efthymiou; Queen Square Genomics; Thomas Schmitt-Mechelke; Andreas Ziegler; Mahmoud Y Issa; Hasnaa M Elbendary; Pasquale Striano; Fowzan S Alkuraya; Maha S Zaki; Joseph G Gleeson; Tahsin Stefan Barakat; Jorgen Bierau; Marjo S van der Knaap; Reza Maroofian; Henry Houlden Journal: Hum Mutat Date: 2022-01-12 Impact factor: 4.700