title: Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function.
abstract: OBJECTIVE
  A pre-treatment determination of the thiopurine S-methyltransferase (TPMT) genotype or phenotype can identify patients at risk of developing severe adverse reactions from thiopurine treatment. The risk of misclassifying a patient might be dependent on the method used. The aim of this study was to investigate the concordance between TPMT genotyping and phenotyping.
  
  
  METHODS
  The data consist of 7195 unselected and consecutive TPMT genotype and phenotype determinations sent to the division of Clinical Pharmacology, Linköping, Sweden. TPMT activity was measured in red blood cells (RBC) and the genotype determined by pyrosequencing for the three most common TPMT variants (TPMT *2, *3A, *3C).
  
  
  RESULTS
  TPMT genotyping identified 89% as TPMT wild type (*1/*1), 10% as TPMT heterozygous and 0.5% as TMPT defective. The overall concordance between genotyping and phenotyping was 95%, while it was 96% among IBD patients (n=4024). Genotyping would have misclassified 8% of the TPMT defectives as heterozygous as compared to 11% if only TPMT activity had been measured. 11% of the heterozygous patients had a normal TPMT activity (>8.9 U/ml RBC) and 3% of the TPMT wild-type patients had an intermediate TPMT activity (2.5-8.9 U/ml RBC).
  
  
  CONCLUSIONS
  There is a risk for TPMT misclassification when only genotyping or phenotyping is used, but it is not reasonable to check both in all patients. Since TPMT genotyping is the more reliable test, especially in TPMT heterozygotes, we suggest that genotyping should be considered the primary choice for the pre-treatment evaluation of TPMT function before initiation of thiopurine therapy.
authors.affiliation: Department of Gastroenterology, Skåne University Hospital, Lund, Sweden. ulf.hindorf@skane.se
authors.forename: Ulf
authors.initials: U
authors.lastname: Hindorf
authors.forename: Malin Lindqvist
authors.initials: ML
authors.lastname: Appell
mesh_terms: D001379:Azathioprine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005819:Genetic Markers; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008658:Inactivation, Metabolic / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D015122:Mercaptopurine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008780:Methyltransferases / Q000097:blood / Q000235:genetics*; D010641:Phenotype; D012189:Retrospective Studies; D013548:Sweden
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine