title: Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study.
abstract: BACKGROUND
  Azathioprine (aza) therapy is beneficial in the treatment of inflammatory bowel disease, but 10%-30% of patients cannot tolerate aza therapy because of adverse drug reactions. Thiopurine S-methyltransferase (TPMT) deficiency predisposes to myelotoxicity, but its association with other side effects is less clear. Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance.
  
  
  METHODS
  We analyzed data from a 6-month prospective study including 71 patients with Crohn disease undergoing first-time aza treatment with respect to aza intolerance. Patients were genotyped for common TPMT and ITPA mutations and had pretherapy TPMT activity measured.
  
  
  RESULTS
  Early drop-out (within 2 weeks) from aza therapy was associated with ITPA 94C > A [P = 0.020; odds ratio (OR), 4.6; 95% confidence interval (95% CI), 1.2-17.4] and low TPMT activity [<10 nmol/(mL erythrocytes . h); P = 0.007; OR = 5.5; 95% CI, 1.6-19.2]. A high-risk group defined by ITPA 94C > A or TPMT <10 nmol/(mL erythrocytes . h) showed significant association with early drop-out (P = 0.001; OR = 11.3; 95% CI, 2.5-50.0) and all drop-outs (P = 0.002; OR = 4.8; 95% CI, 1.8-13.3). For only drop-outs attributable to aza-related side effects (n = 16), there was a significant association with ITPA 94C > A (P = 0.002; OR = 7.8; 95% CI, 2.1-29.1). Time-to-event analysis over the 24-week study period revealed a significant association (P = 0.031) between the time to drop-out and ITPA 94C > A mutant allele carrier status.
  
  
  CONCLUSIONS
  Patients with ITPA 94C > A mutations or low TPMT activity constitute a pharmacogenetic high-risk group for drop-out from aza therapy. ITPA 94C>A appears to be a promising marker indicating predisposition to aza intolerance.
authors.affiliation: Department of Clinical Chemistry, University of Göttingen, Göttingen, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: von Ahsen
authors.forename: Victor W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Christoph
authors.initials: C
authors.lastname: Behrens
authors.forename: Christian
authors.initials: C
authors.lastname: von Tirpitz
authors.forename: Andreas
authors.initials: A
authors.lastname: Stallmach
authors.forename: Hans
authors.initials: H
authors.lastname: Herfarth
authors.forename: Jürgen
authors.initials: J
authors.lastname: Stein
authors.forename: Peter
authors.initials: P
authors.lastname: Bias
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kruis
authors.forename: Max
authors.initials: M
authors.lastname: Reinshagen
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schütz
mesh_terms: D000328:Adult; D000409:Alanine / Q000235:genetics; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D003424:Crohn Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000172:deficiency* / Q000378:metabolism; D010352:Patient Dropouts; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D000097630:Inosine Triphosphatase
chemical_list: D000409:Alanine; D001379:Azathioprine; D003545:Cysteine; D008780:Methyltransferases; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase