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Multiple thiopurine S-methyltransferase variation detection: a step toward personalized medicine.

Genetic polymorphisms play an important role in the variability of drug responses among individuals(1). For thiopurine medications, the enzymatic activity of thiopurine S -methyltransferase (TPMT)1 inactivates thiopurine drugs and is influenced by polymorphisms within the TPMT 2 gene(2). Currently, more than 20 single-nucleotide polymorphisms (SNPs) have been associated with decreased TPMT activity(2). Patients inheriting 2 nonfunctional alleles have undetectable TPMT activity, and standard doses of thiopurines may lead to life-threatening drug toxicities in such patients. To avoid toxicity, investigators have recommended TPMT genotyping to individually tailor the starting drug dosage(2).

In this issue of Clinical Chemistry , Schaeffeler et al. describe the development of a high-throughput genotyping method that can simultaneously detect 22 TPMT polymorphisms affecting TPMT activity(3). Their method consists of 16-plex and 7-plex SNP assays with single-base primer extension and MALDI-TOF mass spectrometric analysis to achieve a high level of multiplexing. All genotypes were correctly detected in control DNA samples and with synthetic templates of known genotypes. In addition, 586 clinical samples were genotyped, and the results were fully concordant with those obtained with denaturing HPLC(3)(4).

The comprehensive genotyping assay of Schaeffeler et al. provides a powerful tool for enhancing TPMT genotype prediction. Although many studies have shown a high …