Thiopurine S-methyltransferase gene polymorphism in Japanese patients with autoimmune liver diseases.
OBJECTIVE
Thiopurine S-methyltransferase (TPMT) genotypes or phenotypes may be a predictive factor for azathioprine-induced toxicities. We investigated the genotypic status of TPMT to evaluate the risk of azathioprine-related adverse effects in Japanese patients with different liver diseases, including autoimmune hepatitis (AIH).


METHODS
49 patients with AIH, 67 with primary biliary cirrhosis (PBC), and 120 with hepatitis C virus (HCV) were examined. TPMT genotypes were determined by PCR-restriction fragment length polymorphism-based assays.


RESULTS
The distribution of TPMT genotypes was 90% TPMT*1/TPMT*1, 8% TPMT*1/TPMT*3C, and 2% TPMT*3C/TPMT*3C in AIH, and 94% TPMT*1/TPMT*1, 4.5% TPMT*1/TPMT*3C, and 1.5% TPMT*3C/TPMT*3C in PBC. All except 1 patient with HCV had the TPMT*1/TPMT*1 genotype. Severe myelosuppression occurred in two of nine patients with AIH who received azathioprine, one of whom was homozygous for TPMT*3C.


CONCLUSIONS
TPMT*3C variants are more frequent in patients with AIH or PBC than in patients with viral hepatitis or healthy volunteers in Japan. Pharmacogenetic screening for TPMT polymorphisms before commencing azathioprine therapy may help to prevent severe hematotoxicity in patients with TPMT deficiency.
Tamori
Akihiro
A
Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan. atamori@med.osaka-cu.ac.jp
Shinzaki
Mayumi
M
Kosaka
Saori
S
Hayashi
Takehiro
T
Iwai
Shuji
S
Enomoto
Masaru
M
Habu
Daiki
D
Sakaguchi
Hiroki
H
Kawada
Norifumi
N
Hino
Masayuki
M
Shiomi
Susumu
S
Nishiguchi
Shuhei
S
D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D044466:Asian People; D001379:Azathioprine / Q000009:adverse effects / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D020022:Genetic Predisposition to Disease; D019693:Hepatitis, Autoimmune / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013921:Thrombocytopenia / Q000139:chemically induced
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine