Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study

BACKGROUND AND AIM: Myelotoxicity has been shown to be very common in Korean patients with inflammatory bowel disease (IBD) during azathioprine (AZA) or 6-mercaptopurine (6-MP) treatment. The purpose of this study was to investigate the relative risk of the thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genotypes and TPMT activity for the development of leukopenia in Korean IBD patients during AZA/6-MP treatment. METHODS: We retrospectively analyzed 286 Korean patients with IBD who had been treated with AZA/6-MP for at least 6 months between June 1996 and September 2006. Common TPMT mutations, including TPMT*1, *2, *3A, *3B, and *3C, and ITPA mutations, including 94C>A and IVS2+21A>C, were determined using a high-performance liquid chromatography method. TPMT activity was measured using liquid chromatography with coupled mass spectrometry/mass spectrometry. RESULTS: Leukopenia occurred in 118 cases (41.3%). TPMT *1/*3C was detected in 7 cases (2.4%), and ITPA 94 C>A was detected in 66 cases (23.1%), including 63 heterozygotes (22.1%) and 3 homozygotes (1.0%). The median TPMT activity was 9.3 U/mL (interquartile range 10.4, range 2.1 to 76.2). Cox regression analysis revealed that patients with heterozygous *3C type TPMT had a higher probability of leukopenia than those with wild type TPMT (P=0.02). Patients with intermediate TPMT activity had a lower probability of leukopenia than those with low activity (P=0.01). However, the ITPA genotype did not affect the risk of leukopenia. CONCLUSIONS: Our data showed that it could be helpful to examine TPMT genotypes and to measure TPMT activity in Korean patients taking AZA/6-MP to predict the development of leukopenia.ope