title: Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age.
abstract: OBJECTIVE
  Thiopurine drugs are commonly used in pediatric patients for the treatment of acute leukemia, organ transplantation and inflammatory diseases. They are catabolized by the cytosolic thiopurine methyltransferase (TPMT), which is subject to a genetic polymorphism. In children, enzyme activities are immature at birth and developmental patterns vary widely from one enzyme to another. The present study was undertaken to evaluate erythrocyte TPMT activity and the correlation between genotype and phenotype in different age groups from birth to adolescence and adulthood.
  
  
  METHODS
  The study included 304 healthy adult blood donors, 147 children and 18 neonates (cord bloods). TPMT activity was measured by liquid chromatography, and genotype was determined using a polymerase chain reaction reverse dot-blot analysis identifying the predominant TPMT mutant alleles (TPMT*3A, TPMT*3B, TPMT*3C, TPMT*2).
  
  
  RESULTS
  There was no significant difference in TPMT activity between cord bloods ( n=18) and children ( n=147) (17.48+/-4.04 versus 18.62+/-4.14 respectively, P=0.424). However, TPMT was significantly lower in children than in adults (19.34+/-4.09) ( P=0.033). In the whole population, there were 91.9% homozygous wild type, 7.9% heterozygous mutants and 0.2% homozygous mutants. The frequency of mutant alleles was 3.0% for TPMT*3A, 0.7% for TPMT*2 and 0.4% for TPMT*3C.
  
  
  CONCLUSIONS
  No impact of child development on TPMT activity could be evidenced, suggesting that TPMT activity is already mature at birth. The difference between children and adults was low with reduced clinical impact expected. When individual TPMT activity was compared with genotype, there was an overlapping region where subjects (4.5%, 12 adults, 9 children) were either homozygous wild type or heterozygous, with a TPMT activity below the antimode value. This result highlighted the importance of measuring TPMT activity to detect all patients at risk of thiopurine toxicity.
authors.affiliation: Laboratoire de Pharmacologie, Hôtel-Dieu, 9 Quai Moncousu, 44093 Nantes cedex 1, France. catherine.ganiere@chu-nantes.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Ganiere-Monteil
authors.forename: Yves
authors.initials: Y
authors.lastname: Medard
authors.forename: Corinne
authors.initials: C
authors.lastname: Lejus
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bruneau
authors.forename: Alain
authors.initials: A
authors.lastname: Pineau
authors.forename: Odile
authors.initials: O
authors.lastname: Fenneteau
authors.forename: Michel
authors.initials: M
authors.lastname: Bourin
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008780:Methyltransferases / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D044465:White People / Q000235:genetics*
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase