title: A pharmacogenetics study of TPMT and ITPA genes detects a relationship with side effects and clinical response in patients with inflammatory bowel disease receiving Azathioprine.
abstract: OBJECTIVE
  Pharmacogenetic studies in inflammatory bowel diseases (IBD) are mainly focused on genes involved in the metabolism of Azathioprine (AZA). Use of AZA is limited by its toxicity, which occurs in 20-30% of patients. Variants in the Thiopurine S-methyltransferase (TPMT) and Inosine triphosphate pyrophosphatase (ITPA) genes have been associated with AZA toxicity, but also can contribute to the lack of response. The aims of this study were to determine the contribution of TPMT and ITPA variants in the development of AZA-related toxicity and response.
  
  
  METHODS
  Variants associated with the decrease of enzyme activity in TPMT and ITPA genes were genotyped with the Snapshot system in 232 IBD patients treated with AZA, and correlated with the clinical response and development of adverse drug reactions in a retrospective case-control study.
  
  
  RESULTS
  Genotypic analysis showed that there is a statistical significance between c.94C > A variant on ITPA gene with non response to AZA treatment (p=0.005) and arthralgia (OR 8.2353; 95%CI 1.752-38.87, p=0.0041), as well as between mutant TPMT alleles and myelosuppression (OR 7.5; 95%CI 1.4456-38.91, p=0.0304).
  
  
  CONCLUSIONS
  There is a positive correlation between c.94C > A variant on ITPA with clinical response. Mutant alleles on TPMT and the variant c.94C > A on ITPA gene predict side effects induced by AZA in our population (myelosuppression and arthralgia).
authors.affiliation: Laboratorio de Genetica Molecular, Unidad de Genetica Medica, Universidad del Zulia, Republica Bolivariana de Venezuela. manubarreiro@hotmail.com
authors.forename: William
authors.initials: W
authors.lastname: Zabala-Fernández
authors.forename: Manuel
authors.initials: M
authors.lastname: Barreiro-de Acosta
authors.forename: Ana
authors.initials: A
authors.lastname: Echarri
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.forename: Aurelio
authors.initials: A
authors.lastname: Lorenzo
authors.forename: Javier
authors.initials: J
authors.lastname: Castro
authors.forename: David
authors.initials: D
authors.lastname: Martínez-Ares
authors.forename: Santos
authors.initials: S
authors.lastname: Pereira
authors.forename: Ignacio
authors.initials: I
authors.lastname: Martin-Granizo
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018771:Arthralgia / Q000139:chemically induced; D001379:Azathioprine / Q000009:adverse effects*; D001853:Bone Marrow / Q000187:drug effects; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D010597:Pharmacogenetics; D011755:Pyrophosphatases / Q000235:genetics*; D012189:Retrospective Studies; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase