The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease.
BACKGROUND
Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients.


METHODS
Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses.


RESULTS
Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with theMRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype(P = 0.049). Of the 15 patients who experienced leucopenia (<3 x 10⁹/l), 7 patients carried the MRP4 variant.The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03–10.57, P = 0.036).


CONCLUSIONS
These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.
Ban
Hiromistu
H
Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, Japan
Andoh
Akira
A
Imaeda
Hirotsugu
H
Kobori
Ayako
A
Bamba
Shigeki
S
Tsujikawa
Tomoyuki
T
Sasaki
Masaya
M
Saito
Yasuharu
Y
Fujiyama
Yoshihide
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000378:metabolism / Q000627:therapeutic use; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics; D005091:Exons; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism / Q000627:therapeutic use; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
D001379:Azathioprine; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human
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