Thiopurine S-methyltransferase polymorphisms: efficient screening method for patients considering taking thiopurine drugs.
OBJECTIVE
More than 11% of the Caucasian population are heterozygous or homozygous carriers of thiopurine S-methyltransferase (TPMT) mutants and are at risk for toxic side effects when treated with thiopurine drugs. Therefore, screening for TPMT polymorphisms in a patient prior to prescribing these agents is recommended. The goal of this study was to determine a cut-off concentration of the TPMT activity assay beyond which genotyping of the TPMT gene should be performed.


METHODS
The TPMT activity of 240 unrelated Caucasian subjects was measured using high-performance liquid chromatography. Genotyping for the most frequent allelic variants, TPMT*2, *3A, *3B, *3C and *7 was performed by LightCycler technology and sequencing.


RESULTS
The inter-individual TPMT activity showed a range from 23 nmol MTG/g*Hb*h(-1) to 97 nmol MTG/g*Hb*h(-1) with a median of 56 nmol MTG/g*Hb*h(-1). Using a cut-off concentration of 45.5 nmol MTG/g*Hb*h(-1), a test sensitivity of 100% and a specificity of 89% were reached for heterozygous carriers of a TPMT mutation. We identified 1 carrier of TPMT*2, 14 carriers of TPMT*3A and 3 carriers of TPMT*3C, resulting in a TPMT heterozygosity prevalence of 7.5%.


CONCLUSIONS
This study defines the cut-off value for the TPMT phenotyping assay at 45.5 nmol/g*Hb*h(-1), beyond which additional genotyping elucidates the individual risk for drug therapy. Using this cut-off concentration, the number of genotyping assays could be reduced by about 60%.
Institute for Clinical Chemistry, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
Barbara
B
Wusk
G A
GA
Kullak-Ublick
C
C
Rammert
A
A
von Eckardstein
M
M
Fried
K M
KM
Rentsch
D005260:Female; D005787:Gene Frequency; D005821:Genetic Techniques; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods; D010641:Phenotype; D011110:Polymorphism, Genetic; D011687:Purines / Q000009:adverse effects* / Q000627:therapeutic use; D012372:ROC Curve; D013557:Switzerland; D044465:White People / Q000235:genetics
D011687:Purines; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase