In a retrospective study of patients with inflammatory bowel disease, van Dieren et al recently reported the absence of a correlation between genotypes for both inosine triphosphate pyrophosphatase (ITPA) and thiopurine methyltransferase (TPMT), with any side effects to azathioprine (AZA) (Gut 2005;54:1664). This contrasts with two other studies. A rigorous prospective study, published recently, has demonstrated a significant association between ITPA genotype and early dropout from AZA therapy.1 Our original publication implicated ITPA in a number of adverse effects, which were independent of myelosuppression.2 Another letter has reported non‐association of ITPA with myelosuppression3 but thiopurine induced myelosuppression has been well documented over the past 25 years as associated with TPMT, not ITPA, status.4
However, we draw attention to a peculiar feature of the TPMT results of van Dieren et al that one patient—who suffered severe myelosuppression—was reported as TPMT*3B/*3B genotype. We previously published a meta‐analysis of the incidence of the TPMT*3B (G460A) mutation,5 discovering that it is rare, and this has been confirmed by a recent large study, making the chance of homozygosity negligible.6 Indeed, our evidence suggested that even the few cases of TPMT*3B may be overreported as a result of a technical problem in TPMT genotyping by polymerase chain reaction‐restriction fragment length polymorphism. Table 1 shows the frequency of TPMT mutant alleles, including TPMT*3B, showing the low frequency of the TPMT*3B allele and apparent cases of overreporting. The TPMT*3A allele, the most common mutant polymorphism among Caucasians, is a double mutant combining an A719G mutation and G460A mutation. The A719G mutation is usually typed by restriction endonuclease digestion that relies on creation of an Acc1 recognition site, and we have shown that this enzyme is prone to failure.5 Failure of A719G recognition will thus result in misreading the TPMT*3A allele as G460A only—that is, as the TPMT*3B allele (and the TPMT*3C allele will be misread as wild‐type TPMT*1).
Table 1 Population frequencies of thiopurine methyltransferase (TPMT) mutant alleles.
| Population group (reference) | TPMT allele frequency (%) | ||||
|---|---|---|---|---|---|
| *2 | *3A | *3B | *3C | *4–19 | |
| Caucasian | |||||
| British (Collie‐Duguid E, et al. Pharmacogen 1999) | 0.5 | 4.5 | 0 | 0.3 | – |
| American (Otterness D, et al. Clin Pharmacol Ther 1997) | 0.17 | 3.2 | 0 | 0.17 | – |
| American (Dervieux T, et al. Clin Chem 2005)6 | 0.26 | 3.6 | 0.006 | 0.91 | – |
| American (Yan L, et al. Clin Pharmacol Ther 2000) | 0 | 3.1 | 0.2 | 0.5 | – |
| European (Spire‐Vayron C, et al. Br J Clin Pharm 1998) | 0.5 | 5.7 | 0 | 0.8 | 0.3 (*7) |
| Spanish (Corominas H, et al. Am J Gastroenterol 2000) | 0 | 4.8 | 0.95 | 3.8 | – |
| Dutch (Corominas H, et al. Am J Gastroenterol 2000) | 0 | 6.5 | 1.9 | 0 | – |
| Polish (Kurzawski M, et al. Ther Drug Monit 2004) | 0.4 | 2.7 | 0 | 0.1 | – |
| Portuguese (Alves S, et al. Clin Pharmacol Ther 2001) | 1 | 2.5 | 0 | 0.7 | – |
| Saami (Loennechen T, et al. Clin Pharmacol Ther 2001) | 0 | 0 | 0 | 3.3 | – |
| Bulgarian (Indjova D, et al. Ther Drug Monit 2003) | 0.16 | 2.24 | 0 | 0.16 | – |
| Italian (Rossi A, et al. Eur J Clin Pharmacol 2001) | 0.48 | 3.9 | 0 | 0.97 | – |
| German (Schaeffeler E, et al. Pharmacogen 2004) | 0.2 | 4.4 | 0 | 0.4 | – |
| South American | |||||
| Brazilian (Boson W, et al. Pharmacogenomics J 2003) | 2.2 | 1.5 | 0.2 | 1 | – |
| Brazil European (Reis M, et al. Pharmacogen 2003) | 0.76 | 2.03 | 0 | 2.54 | – |
| Argentinian (Larovere L, et al. Ann Clin Biochem 2003) | 0.7 | 3.1 | 0 | 0 | 0.3 (*4) |
| Colombian (Isaza C, et al. Meth Find Exp Clin Pharm 2003) | 0.3 | 3.6 | 0 | 0 | – |
| African | |||||
| Afro‐American (Hon Y, et al. Hum Mol Genet 1999) | 0.4 | 0.8 | 0 | 2.4 | 0.2 (*8) |
| Ghanaian (Ameyaw M, et al. Hum Mol Genet 1999) | 0 | 0 | 0 | 7.6 | – |
| Kenyan (McLeod H, et al. Pharmacogen 1999) | 0 | 0 | 0 | 10.1 | – |
| South East Asian | |||||
| Japanese (Kumagai K, et al. Pharmacogen 2001) | 0 | 0 | 0 | 1.6 | – |
| Japanese (Kubota T, Chiba K. Br J Clin Pharmacol 2001) | 0 | 0 | 0 | 0.3 | – |
| Chinese (Collie‐Duguid E, et al. Pharmacogen 1999) | 0 | 0 | 0 | 2.3 | – |
| Asian | |||||
| Uygur Chinese (Zhang J, et al. Eur J Clin Pharmacol 2004) | 0 | 0.3 | 0 | 1.6 | – |
| Han Chinese (Zhang J, et al. Ai Zheng 2003) | 0 | 0 | 0 | 1.33 | – |
| Thai (Chang J, et al. Pharmacogenetics 2002) | 0 | 0 | 0 | 0.6 | – |
| Filipino (Chang J, et al. Pharmacogenetics 2002) | 0 | 0 | 0 | 1 | – |
| Chinese (Kham S, et al. J Pediatr Hematol Oncol 2002) | 0 | 0 | 0 | 3 | – |
| Malay (Kham S, et al. J Pediatr Hematol Oncol 2002) | 0 | 0 | 0 | 2.3 | 0.2 (*6) |
| South West Asian | |||||
| Indian (Kham S, et al. J Pediatr Hematol Oncol 2002) | 0 | 0.5 | 0 | 0.8 | – |
| British SW Asian (Collie‐Duguid E, et al. Pharmacogen 1999) | 0 | 1 | 0 | 0 | – |
| British Asian (Marinaki A, et al. Pharmacogen 2003)2 | 0 | 0.6 | 0 | 2.3 | – |
Curiously, van Dieren et al state that pre‐therapy TPMT genotyping is “of limited clinical value” but their results do not support this statement, as two cases of severe and potentially life threatening myelosuppression in their patient group were predicted by TPMT genotyping. In the absence of sequencing evidence, some doubt remains over the other TPMT genotype results presented. TPMT requesting has become routine in some large scale clinical practices, particularly in combination with thioguanine nucleotide monitoring.6,7,8 But until extensive and preferably prospective studies are accumulated in the literature it seems too early to dismiss the full pharmacogenetic value of ITPA and TPMT. We keenly await further publications elucidating genetic regulation of thiopurine metabolism as a valuable pharmacogenetic model.
Footnotes
Conflict of interest: None declared.
References
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