Evaluating Frequencies of Thiopurine S-Methyl Transferase (TPMT) Variant Alleles in Israeli Ethnic Subpopulations Using DNA Analysis

摘要

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-methyt transferase. A number of single nucleotide substitutions encoding variant enzymes account for most enzyme deficiencies. Objectives: To determine the frequency of individuals from different Israeli ethnic groups who may be at risk for drug toxicity from drugs of the tbioguanide family due to enzymatic variants.Methods: DNA analysis was performed using polymerase chain reaction methods. We tested TPMT atlelic variants TPMT*3A (6460A, A719G), TPMT*3B (G460A) and TPMT*3C (A719G) in five subpoputations in Israel: mixed-origin Israeli Jews, Arabs, Druze, Jews of Kurdish extraction, and Ethiopian Jews. Results: The Oruze (P = 0.0002) and Ethiopian Jewish (P=0.015) subpopulations had a significantly unique dis- : tribution of altelic variants compared to the fest of the Israeli population. The Druze subpopulation showed a high number of TPMT variants with decreased activity, and a homozygote forTPMT*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 forother Israeli ethnic subgroups.