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

Potočnik, Uroš; Ferkolj, Ivan; Glavač, Damjan; Dean, Michael

doi:10.1038/sj.gene.6364123

Cited by 159 publications

(147 citation statements)

References 33 publications

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“…A slight, but statistically insignificantly increased value of 54% in the mutant allele T was only seen in patients with UC (OR: 1.76, CI: 0.30 -9.78, p< 0.46). Glas et al [47] and Potocnik et al [24] have reported similar ratios. …”

Section: Mdr1 C3435tsupporting

confidence: 58%

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Determination of the Single Nucleotide Polymorphisms C3435 and G2677T in MDR1 and C421A in BCRP in Blood Samples of Patients with Inflammatory Bowel Disease and Healthy Controls in the Swiss Population

2012

J Postgenom Drug Biomark Develop

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Aims: P-glycoprotein (P-gp, ABCB1, MDR1) and breast cancer resistance protein (BCRP, ABCG2) protect the luminal cells of the gastro-intestinal tract from potentially toxic substances. Genetic polymorphisms have previously been associated with disease susceptibility, severity, and treatment prognosis of inflammatory bowel disease. We investigated the prevalence of frequent single nucleotide polymorphisms of P-gp and BCRP in the Swiss population in healthy volunteers (n = 17) and patients newly diagnosed with Crohn's Disease (CD, n = 34) or Ulcerative Colitis (UC, n = 38). Methods: DNA from peripheral blood cells was used to assess genotype and allele frequencies of MDR1 C3435T, MDR1 G2677T, and BCRP C421A. Results: Weak associations for BCRP C421A (p < 0.18) and MDR1 G2677T (p < 0.27) were seen in UC and a trend towards the wild type allele for MDR1 C3435T (p < 0.46). MDR1 3435CC / BCRP 421CC (Χ2: 1.0142, p < 0.30) in UC and MDR1 2677G / BCRP 421A (Χ2: 1.5615, p < 0.22) also weakly correlated with UC. Results for BCRP C421A in particular justify further study. Conclusions: Trends towards certain alleles and haplotypes were seen. These merit further studies in larger subgroups (e.g. by disease stage, therapy refractory patients, etc.). In the human gastrointestinal tract, P-gp is expressed predominantly apically on the epithelium of small intestine and colon, but also in the small biliary and pancreatic ductules [10]. P-gp is therefore seen as a contributor to gut mucosal defense and reduced activity is thought to be a co-factor in IBD pathogenesis [11]. P-gp is encoded by the MDR1/ABCB1 gene, located on Chromosome 7q21.1, and spans over 100 kb. However, MDR1 mRNA has a size of 4.7 kDa, implying that only a small percentage of the gene actually codes [12]. P-gp is currently the best studied ABC transporter and to date 50 single nucleotide polymorphisms (SNPs) have been identified, more than half of which reside in the coding region [13][14][15]. This interest stems from its ability to confer multidrug resistance in cancer cells by lowering the uptake of anti-cancer drugs [16]. Due to its promiscuity and localization, it also affects the bioavailability of many other drugs [17] and exposure to one of its substrates can render the cell resistant to a wide range of compounds [18]. AbstractAims: P-glycoprotein (P-gp, ABCB1, MDR1) and breast cancer resistance protein (BCRP, ABCG2) protect the luminal cells of the gastro-intestinal tract from potentially toxic substances. Genetic polymorphisms have previously been associated with disease susceptibility, severity, and treatment prognosis of inflammatory bowel disease. We investigated the prevalence of frequent single nucleotide polymorphisms of P-gp and BCRP in the Swiss population in healthy volunteers (n = 17) and patients newly diagnosed with Crohn's Disease (CD, n = 34) or Ulcerative Colitis (UC, n = 38).Methods: DNA from peripheral blood cells was used to assess genotype and allele frequencies of MDR1 C3435T, MDR1 G2677T, and BCRP C421A.Results: Weak ass...

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Section: Mdr1 C3435tsupporting

confidence: 58%

“…MDR1 G2677A is not equally well understood as its prevalence is very low (around 1%) [12] and high sample sizes are needed to give valid estimates. Some authors therefore chose to exclude it in their studies [23,24].…”

Section: P-glycoprotein (P-gp Mdr1)mentioning

confidence: 99%

Determination of the Single Nucleotide Polymorphisms C3435 and G2677T in MDR1 and C421A in BCRP in Blood Samples of Patients with Inflammatory Bowel Disease and Healthy Controls in the Swiss Population

2012

J Postgenom Drug Biomark Develop

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“…In another study, haplotype 1236T/2677G/3435T carriers demonstrated higher P-gp activity when compared to non-carriers [14]. The 1236T/2677T/3435T haplotype was also shown to be associated with a slightly greater risk of developing refractory Crohn's disease (P=0.044) [26]. The same study showed that when each SNP occurred separately, there was no significant correlation with the development of the disease.…”

Section: Introductionmentioning

confidence: 59%

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

et al. 2006

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Introduction-The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related.

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“…Present approaches have not been able to discern whether these other genes or the class Ⅱ genes are the true risk genes in the HLA locus. [79][80][81][82] , multiple polymorphisms in the MDR1/ABCB1 gene on chromosome 7q [83][84][85][86][87][88][89][90][91][92] , and polymorphisms in the DLG5 gene on chromosome 10q [70,[93][94][95][96][97][98][99][100][101][102] . (See section C.4.1.)…”

Section: Hla Associationsmentioning

confidence: 99%

Inflammatory bowel disease: Genetic and epidemiologic considerations

Cho

2008

WJG

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Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn's disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.

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

Cited by 159 publications

References 33 publications

Determination of the Single Nucleotide Polymorphisms C3435 and G2677T in MDR1 and C421A in BCRP in Blood Samples of Patients with Inflammatory Bowel Disease and Healthy Controls in the Swiss Population

Determination of the Single Nucleotide Polymorphisms C3435 and G2677T in MDR1 and C421A in BCRP in Blood Samples of Patients with Inflammatory Bowel Disease and Healthy Controls in the Swiss Population

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

Inflammatory bowel disease: Genetic and epidemiologic considerations

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