title: Evaluating frequencies of thiopurine S-methyl transferase (TPMT) variant alleles in Israeli ethnic subpopulations using DNA analysis.
abstract: BACKGROUND
  Traditionally, medication dosage was based on clinical and demographic parameters, but drug metabolism was recently recognized as an important factor for proper dosing and prediction of side effects. Metabolic considerations are crucial when administering drugs with a narrow therapeutic index, such as those of the thioguanides family (azathioprine and 6-MP). These can cause life-threatening myelosuppression due to low activity of a critical metabolic enzyme, thiopurine S-methyl transferase. A number of single nucleotide substitutions encoding variant enzymes account for most enzyme deficiencies.
  
  
  OBJECTIVE
  To determine the frequency of individuals from different Israeli ethnic groups who may be at risk for drug toxicity from drugs of the thioguanide family due to enzymatic variants.
  
  
  METHODS
  DNA analysis was performed using polymerase chain reaction methods. We tested TPMT allelic variants TPMT*3A (G460A, A719G), TPMT*3B (G460A) and TPMT*3C (A719G) in five subpopulations in Israel: mixed-origin Israeli Jews, Arabs, Druze, Jews of Kurdish extraction, and Ethiopian Jews.
  
  
  RESULTS
  The Druze (P = 0.0002) and Ethiopian Jewish (P = 0.015) subpopulations had a significantly unique distribution of allelic variants compared to the rest of the Israeli population. The Druze subpopulation showed a high number of TPMT variants with decreased activity, and a homozygote for TPMT*3A/ *3A was detected. Ethiopian Jews were found to carry mainly the TPMT*3C variant, also observed in other studies of African populations.
  
  
  CONCLUSIONS
  It is advisable that Druze patients be tested for the TPMT enzyme before starting treatment with 6-MP or azathioprine. Such testing may also be considered for other Israeli ethnic subgroups.
authors.affiliation: Hebrew University Medical School, Hadassah-Hebrew University Medical Center (Ein Kerem Campus), Jerusalem, Israel.
authors.forename: Ofri
authors.initials: O
authors.lastname: Ronen
authors.forename: Sara Bar
authors.initials: SB
authors.lastname: Cohen
authors.forename: Deborah
authors.initials: D
authors.lastname: Rund
mesh_terms: D005006:Ethnicity / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics*; D006801:Humans; D007557:Israel; D008780:Methyltransferases / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods*
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase