Multidrug resistance 1 gene in inflammatory bowel disease: A meta-analysis

Abstract

The MDR1 gene is an attractive candidate gene for the pathogenesis of inflammatory bowel disease (IBD) and perhaps response to therapy, with evidences at both functional and genetic levels. Its product, the P-glycoprotein (P-gp) functions as a transmembrane efflux pump thus influencing disposition and response of many drugs, some of whom (i.e. glucocorticoids) central to IBD therapy. In addition P-gp is highly expressed in many epithelial surfaces, included gastrointestinal tract (G-I) with a putative role in decreasing the absorption of endogenous or exogenous toxins, and perhaps host-bacteria interaction. Many genetic variations of MDR1 gene has been described and in some instances evidences for different P-gp expression as well drugs metabolism have been provided. However data are often conflicting due to genetic heterogeneity and different methodologies employed. Perhaps the greatest piece of evidence of the physiological importance of P-gp in the G-I tract has come from the description of the mdr1 knock-out mice model, which develops a spontaneous colitis in a specific pathogen-free environment. Studies investigating MDR1 gene polymorphism and predisposition to IBD have also shown conflicting results, owing to the known difficulties in complex diseases, especially when the supposed genetic contribution is weak. In this study we have undertaken a meta-analysis of the available findings obtained with two SNPs polymorphism (C3435T and G2677T/A) in IBD; a significant association of 3435T allele and 3435TT genotype has been found with UC (OR = 1.17, P = 0.003 and OR = 1.36, P = 0.017, respectively). In contrast no association with CD and the G2677T/A polymorphism could be demonstrated.

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

“…In contrast, the effects on cyclosporine pharmacokinetics are more complex: Overall, there was no effect of the c.3435C>T ABCB1 polymorphism on the pharmacokinetic parameters, although the total cyclosporine bioavailability (AUC 0-12 ) was slightly reduced (table 3) [101]. Furthermore, the c.3435C>T polymorphism was found to be associated with a minimal increase in the risk for ulcerative colitis or breast cancer in Caucasians [102][103][104]. Taken together, the c.3435C>T…”

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

“…Even though C3435T is a silent SNP, early studies [20] showed a decrease in duodenal MDR1 protein expression. Reasons for its effects are still subject of debate [21] and a possible link between this SNP and IBD is also inconclusive [12].…”

“…There are indications that the MDR1 G2677T allele is in linkage disequilibrium with C3435T, offering a possible explanation for loss of activity associated with this silent SNP [22]. 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].…”

“…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].…”

Effect of RANTES gene promoter genotypes in patients with ulcerative colitis

“…The genetic predisposition to inflammatory bowel diseases has been well-established through epidemiological studies and genome-wide linkage analyses; however, the accountable genes require further analyses (4). Therefore, the association between the polymorphism of various genes and UC has been studied previously (5)(6)(7)(8)(9)(10)(11).…”