Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease.
OBJECTIVE
Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S-methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA.


METHODS
The frequency of TPMT mutations was investigated in 147 Japanese inflammatory bowel disease (IBD) patients retrospectively. In these subjects, the presence of four mutant alleles (TPMT*2, *3B, *3C and *8) was determined by direct sequencing. The incidence of adverse reactions among patients carrying wild-type TPMT was investigated. The blood level of 6-thioguanine nucleotide (6-TGN) was measured and analyzed in 47 patients with wild-type TPMT. The results were analyzed in relation to the concomitant use of aminosalicylates (ASA).


RESULTS
Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/*1) and three (2.0%) carried a mutant TPMT allele (TPMT*1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC < or = 3000/microL) was seen in 15.8% of the patients with wild-type TPMT. 6-TGN levels varied among 47 patients with wild-type TPMT. The blood levels of 6-TGN were significantly higher in the patients receiving concomitant ASA treatment compared with those not receiving concomitant ASA treatment (P = 0.0033).


CONCLUSIONS
The frequency of TPMT gene mutations is low among Japanese IBD patients. The incidence of adverse reactions to AZA was high, even in patients carrying wild-type TPMT. It is concluded that determination of TPMT genotype may not be useful in Japanese IBD patients to predict adverse reactions to AZA.
Takatsu
Noritaka
N
Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan. syokaki@fukuoka-u.ac.jp
Matsui
Toshiyuki
T
Murakami
Yuji
Y
Ishihara
Hiroshi
H
Hisabe
Takashi
T
Nagahama
Takashi
T
Maki
Shinichirou
S
Beppu
Takahiro
T
Takaki
Yasuhiro
Y
Hirai
Fumihito
F
Yao
Kenshi
K
D000328:Adult; D000505:Alopecia / Q000139:chemically induced / Q000235:genetics; D000636:Aminosalicylic Acids / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D044466:Asian People; D001379:Azathioprine / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury; D003141:Communicable Diseases / Q000139:chemically induced / Q000235:genetics; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000178:diet therapy* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics; D007564:Japan; D007970:Leukopenia / Q000139:chemically induced / Q000235:genetics; D008107:Liver Diseases / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D013873:Thionucleotides / Q000097:blood; D055815:Young Adult
D000636:Aminosalicylic Acids; D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine