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

Abstract

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...