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

Authors
 Jae Hak Kim  ;  Jae Hee Cheon  ;  Seong Soo Hong  ;  Chang Soo Eun  ;  Jeong-Sik Byeon  ;  Sung Yi Hong  ;  Bo-Young Kim  ;  Soon-ho Kwon  ;  Seung Won Kim  ;  Dong Soo Han  ;  Suk-Kyun Yang  ;  Won Ho Kim 
Citation
 JOURNAL OF CLINICAL GASTROENTEROLOGY, Vol.44(10) : 242-248, 2010 
Journal Title
JOURNAL OF CLINICAL GASTROENTEROLOGY
ISSN
 0192-0790 
Issue Date
2010
MeSH
Academic Medical Centers ; Adolescent ; Adult ; Anti-Inflammatory Agents/adverse effects* ; Anti-Inflammatory Agents/pharmacokinetics ; Asian Continental Ancestry Group/genetics* ; Chi-Square Distribution ; Chromatography, High Pressure Liquid ; Female ; Gastrointestinal Agents/adverse effects* ; Gastrointestinal Agents/pharmacokinetics ; Genetic Predisposition to Disease ; Heterozygote ; Homozygote ; Humans ; Inflammatory Bowel Diseases/drug therapy* ; Inflammatory Bowel Diseases/enzymology ; Inflammatory Bowel Diseases/ethnology ; Inflammatory Bowel Diseases/genetics ; Kaplan-Meier Estimate ; Leukopenia/chemically induced* ; Leukopenia/ethnology ; Leukopenia/genetics ; Male ; Mercaptopurine/adverse effects* ; Mercaptopurine/analogs & derivatives* ; Mercaptopurine/pharmacokinetics ; Methyltransferases/genetics ; Methyltransferases/metabolism* ; Phenotype ; Proportional Hazards Models ; Pyrophosphatases/genetics ; Pyrophosphatases/metabolism ; Republic of Korea ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Tandem Mass Spectrometry ; Treatment Outcome ; Young Adult
Keywords
azathioprine ; 6-mercaptopurine ; leukopenia ; thiopurine methyltransferase ; inflammatory bowel disease
Abstract
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.
Full Text
http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&AN=00004836-201011000-00004&LSLINK=80&D=ovft
DOI
10.1097/MCG.0b013e3181d6baf5
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Others (기타) > 1. Journal Papers
Yonsei Authors
Kim, Seung Won(김승원) ORCID logo https://orcid.org/0000-0002-1692-1192
Kim, Won Ho(김원호) ORCID logo https://orcid.org/0000-0002-5682-9972
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/102875
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