The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Ban, Hiromistu; Andoh, Akira; Imaeda, Hirotsugu; Kobori, Ayako; Bamba, Shigeki; Tsujikawa, Tomoyuki; Sasaki, Makoto; Saito, Yasuharu; Fujiyama, Yoshihide

doi:10.1007/s00535-010-0248-y

Cited by 94 publications

(96 citation statements)

References 29 publications

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“…Direct sequence analyses in our laboratory indicated that the allelic frequency of MRP4 G2269A was 14.7% in the Japanese population (24). In IBD patients treated with AZA/6-MP, the WBC count was significantly lower in patients with the MRP4 G2269A SNP than in patients with a wild allelotype (24).…”

Section: Introductionmentioning

confidence: 77%

“…In particular, Japanese populations are sensitive to thiopurines, and relatively lower doses of AZA (0.6-1.2 mg/kg/day) are recommended for the treatment of Japanese IBD patients (11). Similar to TPMT A719G and ITPase C94A, we recently showed that MRP4 G2269A is a new factor accounting for heightened thiopurine sensitivity in Japanese patients with IBD (24). Although the SNPs accounting for thiopurine sensitivity have been reported as important factors for individualizing therapy to minimize adverse effects and to maximize clinical response, a rapid and clinically applicable method for the SNP genotyping of these genes has not yet been established.…”

Section: Discussionmentioning

confidence: 96%

“…Rapid and cost-effective methods must be developed for genotyping, and it would be desirable to include this information in patient records as a guide for physicians to individualize treatment. We previously utilized polymerase-chain reaction-restriction fragment length polymorphism (PCR-RFLP) analyses for the determination of the TPMT and ITPase genotypes (24)(25)(26), and used direct-sequencing analysis for MRP4 (24). However, these methods require multiple steps and are time-consuming.…”

Section: Introductionmentioning

confidence: 99%

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Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Osaki¹,

Imaeda²,

Ban³

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Thiopurine drugs are the most common drugs used to maintain clinical remission in inflammatory bowel disease (IBD). Three single-nucleotide polymorphisms (SNPs), TPMT A719G (rs1142345), inosine triphosphate pyrophosphatase (ITPase) C94A (rs1127354) and multidrug resistance protein 4 MRP4 G2269A (rs3765534), have been reported to account for heightened sensitivity to thiopurine drugs in the Japanese population. We investigated the usefulness of the TaqMan ® PCR assay (Applied Biosystems) for the rapid detection of these SNPs to improve the safety of thiopurine therapy. We enrolled 44 healthy volunteers and 235 IBD patients. Genotyping of the SNPs was performed using Custom TaqMan SNP genotyping assays, direct sequencing and PCR-RFLP. Genotyping for MRP4 G2269A by the TaqMan PCR assay was successfully achieved in all samples. Comparison with our previous data using direct sequencing indicated one discordant result, and re-sequencing showed that the TaqMan PCR assay was correct. The overall accuracy of the TaqMan assay for MRP4 G2269A was 100%. The TaqMan PCR genotyping for TPMT A719G and ITPase C94A was successfully performed in all samples. The results of TPMT A719G by the TaqMan assay were identical with those of PCR-RFLP. In ITPase C94A, a comparison of the TaqMan assay and PCR-RFLP yielded 12 discordant results, and direct sequencing showed that the TaqMan PCR assay was correct. The allelic frequency determined by the TaqMan assay was 0.145 for MRP4 G2269A, 0.009 for TPMT A719G and 0.121 for ITPase C94A, respectively. In conclusion, the TaqMan ® PCR assay is useful for genotyping of SNPs responsible for thiopurine sensitivity in Japanese IBD patients.

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Section: Introductionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Osaki¹,

Imaeda²,

Ban³

et al. 2011

Experimental and Therapeutic Medicine

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“…In 403 patients with breast cancer, cyclophosphamide-induced adverse drug reactions were associated with ABCC4 polymorphisms [168], and the c.2269A allele of ABCC4 was associated with significantly lower white blood cell counts and with higher erythrocyte content of 6-thioguanine nucleotide in a cohort of 235 patients suffering from inflammatory bowel disease [169].…”

Section: Later a Study In 95 Caucasians Reported 74 Variations Includmentioning

confidence: 99%

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Stieger

Meier

2011

Pharmacogenomics

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This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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“…Studies show that single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) locus are associated with anemia in patients treated with combination therapy (12)(13)(14). Two SNPs that are associated with ITPA enzyme activity were identified in the Caucasian population (12), but the Japanese population lacks one of these SNPs (14,15). A limited number of reports have demonstrated the association of ITPA genotypes with RBV-induced anemia, but further studies concerning the role of ITPA genotypes on RBV-induced anemia are required.…”

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confidence: 99%

Polymorphism of the inosine triphosphate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients

et al. 2011

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Abstract. Ribavirin (RBV)-induced anemia is a serious side effect of pegylated interferon (PEG-IFN) plus RBV therapy which is the standard care most effective for hepatitis C virus (HCV) infection. In the present study, we investigated the association of inosine triphosphate pyrophosphatase (ITPA) genotypes with RBV-induced hemoglobin (Hb) reduction in HCV patients treated with PEG-IFN/RBV therapy. The genotypes of the ITPA rs1127354 single nucleotide polymorphism were determined in 179 patients with HCV infection. Among them, 52 patients were treated with PEG-IFN/RBV. The frequency of the ITPA major allele (CC) was 76.3% and that of the minor allele (CA and AA) was 23.7%. A rapid decrease in Hb levels during the initial 4 weeks was observed in patients with the ITPA major allele (CC), but not in patients with the ITPA minor allele (C/A and AA). Hb levels at 4 weeks were significantly lower in patients with the ITPA major allele than the levels in patients with the minor allele. Out of the 41 patients, 6 (14.6%) with ITPA major allele had Hb levels <10 g/dl and 11 patients (26.8%) had a decline in Hb of >3 g/dl. None of the patients with the ITPA minor allele had such data. There were no significant differences in virological responses of HCV-RNA between patients with the ITPA major allele and those with the minor allele. In conclusion, the ITPA genotypes may be a useful marker for prediction of RBV-induced anemia. IntroductionHepatitis C virus (HCV) is the leading cause of chronic liver disease. It accounts for 70% of all chronic hepatitis cases, 40% of all cases of liver cirrhosis and 60% of hepatocellular carcinomas (HCC) (1,2). Since the successful eradication of HCV is associated with a reduced risk of liver cirrhosis and HCC (3,4), antiviral therapy plays a crucial role in the management of HCV-infected patients. Currently, pegylated interferon (PEG-IFN) plus ribavirin (RBV) is considered to be the standard of care most effective for chronic hepatitis C (5-7), but the rate of sustained virological response (SVR; HCV RNA negative for 24 weeks after the cessation of therapy) is approximately 50% in patients with HCV genotype 1, the most common genotype found in populations in many countries (5,6). Furthermore, 20-30% of HCV genotype 1 patients are non-responders to PEG-IFN/RBV therapy (3).PEG-IFN therapy sometimes causes bone marrow suppression (8,9), and dose reduction may be required in such cases. However, dose reduction is associated with a potentially compromised treatment outcome. Rates of viral clearance are significantly reduced in patients who cannot be maintained on at least 80% of their PEG-IFN/RBV dosage for the duration of treatment (10). Prediction of risk for such complications would be clinically useful for selecting patients for therapy, as well as planning the monitoring frequency. Since bone marrow suppression remains prevalent in patients with early-stage fibrosis, a genetic biomarker for predicting risk of treatment for bone marrow suppression would be particularly useful at the start of...

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The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Abstract: These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.

Cited by 94 publications

References 29 publications

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Polymorphism of the inosine triphosphate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients

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