title: Thiopurine S-methyltransferase (TPMT) activity is better determined by biochemical assay versus genotyping in the Jewish population.
abstract: BACKGROUND
  Thiopurine S-methyltransferase (TPMT) is a key enzyme that deactivates thiopurines, into their inactive metabolite, 6-methylmercaptopurine. Intermediate and low TPMT activity may lead to leukopenia following thiopurine treatment. The aim of this study was to determine TPMT activity and TPMT alleles (genotype-phenotype correlation) in Jews, aiming to develop an evidence-based pharmacogenetic assay for this population.
  
  
  METHODS
  TPMT activity was determined in 228 Jewish volunteers by high performance liquid chromatography. Common allelic variants in the Caucasian population [TPMT*2 (G238C), TPMT *3A (G460A and A719G), TPMT* 3B (G460A) and TPMT*3C (A719G)] were tested. Phenotype-genotype correlation was examined and discordant cases were fully sequenced to identify novel genetic variants.
  
  
  RESULTS
  Mean TPMT activity was 15.4 ± 4 U/ml red blood cells (range 1-34). Intermediate activity was found in 33/228 (14%) subjects and absent activity was found in one sample (0.4%). Only eight individuals (3.5% of the entire cohort and 24% of those with intermediate/low activity) were identified as carriers of a TPMT genetic variant, all of whom had the TPMT*3A allele. Sequencing the entire TPMT coding region and splice junctions in the remainder of the discordant cases did not reveal any novel variants.
  
  
  CONCLUSIONS
  Genotyping TPMT in Jews yields a much lower rate of variants than identified in the general Caucasian population. We conclude that a biochemical assay to determine TPMT enzymatic activity should be performed in Jews before starting thiopurine treatment in order to identify low activity subjects.
authors.affiliation: Pediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Center, The Hebrew University, P.O. B 3235, 91031, Jerusalem, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Kasirer
authors.forename: Rephael
authors.initials: R
authors.lastname: Mevorach
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Nurit
authors.initials: N
authors.lastname: Algur
authors.forename: Devora
authors.initials: D
authors.lastname: Soiferman
authors.forename: Rachel
authors.initials: R
authors.lastname: Beeri
authors.forename: Yelana
authors.initials: Y
authors.lastname: Rachman
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.forename: Dan
authors.initials: D
authors.lastname: Turner
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010597:Pharmacogenetics
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase