Common single nucleotide polymorphisms of the MDR1 gene have no influence on its mRNA expression level of normal kidney cortex and renal cell carcinoma in Japanese nephrectomized patients

Uwai, Yuichi; Masuda, Satohiro; Goto, Maki; Motohashi, Hideyuki; Saya, Hideyuki; Okuda, Masahiro; Nakamura, Eijirou; Ito, Noriyuki; Ogawa, Osamu; Inui, Ken Ichi

doi:10.1007/s10038-003-0105-4

Cited by 26 publications

(26 citation statements)

References 22 publications

(27 reference statements)

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“…24,25 We also believe that including intronic SNPs 7 and 8 and haplotypes defined by these two SNPs in analysis of P-gp functional expression might help to better understand the functional consequences of MDR1 polymorphisms. Uwai et al 26 suggested intron 16 poly- MDR1 polymorphisms in Crohn disease and ulcerative colitis U PotoWnik et al 535 morphism (SNP8 in our study)-dependent downregulation of P-gp expression in the kidney cortex during tumor development. However, the expression and functional data to date are mainly available for coding SNPs in exons 21 and 26.…”

Section: Discussionsupporting

confidence: 50%

Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis

et al. 2004

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We used coding and noncoding polymorphisms evenly spaced across the ABCB1/MDR1 gene to perform association analysis in Slovenian patients with inflammatory bowel diseases and to obtain haplotype structure and patterns of linkage disequilibrium (LD) in the MDR1 gene. A disease association study was performed in 307 IBD patients, including 144 patients with ulcerative colitis (UC) and 163 patients with Crohn's disease (CD), and 355 healthy controls. Here we report an association between MDR1 alleles, polymorphisms and haplotypes and refractory CD patients, who do not respond to standard therapy, including patients who develop fistulas. We also report an association with UC and MDR1 polymorphisms in a Slovenian population. Haplotypes significantly associated with diseases were defined by single-nucleotide polymorphisms (SNPs) in exons 12 (1236 C4A), 21(A893S), and 26 (3435 C4T). In addition, two intronic SNPs in LD with the disease haplotype, one in intron 13 (rs2235035) and another in intron 16 (rs1922242), were significantly associated with refractory Crohn (P ¼ 0.026, odds ratio (OR) 2.7 and P ¼ 0.025, OR 2.8, respectively), as well as with UC (P ¼ 0.006, OR 1.8 and P ¼ 0.026, OR 1.9, respectively). Our results suggest that MDR1 is a potential target for therapy in refractory CD patients and in patients with UC.

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Section: Discussionsupporting

confidence: 50%

Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis

et al. 2004

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“…11,12 Very recently, it was shown that the 3435C4T polymorphism may influence mRNA stability. 13 The influence of ABCB1 polymorphisms on expression and function in kidney tissue was examined in a Japanese sample, showing no influence on mRNA expression in normal kidney cortex as well as in renal cell carcinoma (RCC) tissue, 14 whereas in a German sample, a strong association of ABCB1 3435C4T to the risk of non-clear-cell renal cell carcinoma (non-CCRCC) was described. 15 To our knowledge, there is no data available on the significance of ABCC2 variants to MRP2 expression or function in normal renal tissue or in renal cancer.…”

Section: Introductionmentioning

confidence: 99%

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

et al. 2006

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There is increasing evidence that polymorphisms of the adenosine 5 0 triphosphate membrane transporters ABCB1 (P-glycoprotein, MDR1) may affect expression and function, whereas less information is available about the impact of ABCC2 (multidrug resistance-associated protein (MRP2)) single-nucleotide polymorphisms . Particularly, their role in human kidney for drug elimination and in the etiology of renal cell carcinoma is poorly understood. ABCB1 and ABCC2 mRNA and protein expression levels were determined by real-time polymerase chain reaction or immunohistochemistry in kidney cancer and adjacent unaffected cortex tissue of 82 nephrectomized renal cell cancer (RCC) patients (63 clear-cell RCC (CCRCC), 19 non-CCRCC). The DNA of all patients was genotyped for ABCB1 À2352G4A, À692T4C, 2677G4T/A (Ala893Ser/Thr), and 3435C4T, and ABCC2 À24C4T, 1249G4A (Val417Ile) and 3972C4T. ABCB1 and ABCC2 were less expressed in CCRCC than in normal cortex on mRNA as well as on protein level. Although the overall genotype frequency distribution did not differ between the patients and a matched control group, ABCB1 2677T/ A and 3435T genotypes were associated with higher (P ¼ 0.02 and P ¼ 0.04) and ABCC2 À24 T with lower mRNA levels in normal tissues (0.03). The expression of ABCB1 and ABCC2 was not related to genetic variants in RCC tissue. In a reporter gene assay in HepG2 cells, the ABCC2 À24T construct showed an 18.7% reduced activity (P ¼ 0.003). In conclusion, ABCB1 and ABCC2 genotypes modulate the expression in the unaffected renal cortex of RCC patients, possibly contributing to inter-individual differences in drug and xenobiotics elimination. Their role in RCC cancer susceptibility or chemotherapy resistance needs further elucidation.

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“…18 Two studies have described the opposite association, that is, the T polymorphism associated with increased mRNA expression, but once again these have been either nonsignificant 19 or performed on a very small sample. 20 The majority have failed to find an association, 17,[21][22][23][24][25] although two of these negative studies did show an association with haplotype rather than genotype. 17,21 Most studies of the 2677G4TA polymorphism and mRNA expression levels have also been negative, 17,19,21,[23][24][25] although one study 22 did report an association between the GG2677 genotype and reduced mRNA expression.…”

Section: Effects Of Genotype On Abcb1 Mrna and Protein Expressionmentioning

confidence: 99%

“…Associations with other polymorphisms in the ABCB1 gene have been equally inconclusive. The majority of studies have failed to show a significant association between 2677G4TA and mRNA expression 17,19,21,[23][24][25] or with PGP expression. 17,23,24,26,27 Other ABCB1 polymorphisms have similarly also failed to demonstrate positive associations.…”

Section: Gd Leschziner Et Almentioning

confidence: 99%

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

et al. 2006

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The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

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Common single nucleotide polymorphisms of the MDR1 gene have no influence on its mRNA expression level of normal kidney cortex and renal cell carcinoma in Japanese nephrectomized patients

Cited by 26 publications

References 22 publications

Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis

Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

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