Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

Abstract

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.

Genotype and allele frequencies of MDR1 gene C1236T polymorphism in a Turkish population

“…To date, the most commonly reported polymorphism linked to different responses of patients to various MDR1 substrates is located at exon 26, C3435T, and does not result in an amino acid change. This silent polymorphism has been found to differ significantly amongst different populations (Tang et al, 2002;Jamroziak et al, 2004;Ramasamy et al, 2006;Kimchi-Sarfaty et al, 2007b). However, C3435T SNP has been associated with changes in the expression of MDR1 (Hoffmeyer et al, 2000;Larsen et al, 2007).…”

“…A number of SNPs in the MDR1 gene have already been identified as clinically important for drug response, raising the need for the genotyping of these SNPs in different populations for individualized drug treatment (Kimchi-Sarfaty et al, 2007b). Drug pharmacokinetics involving P-gp has often been found to be affected in individuals carrying various non-silent SNPs; however, sometimes changes have also been observed in individuals carrying silent SNPs (Komar, 2007a).…”

“…Human P-gp is encoded by the MDR1 gene, which is located on chromosomal region 7q21 and consists of 28 exons ranging in size from 49 to 209 bp, and the cDNA spans 4.5 kb (Ambudkar et al, 2003;Ishikawa et al, 2004;Kimchi-Sarfaty et al, 2007b). To date, over 50 single nucleotide polymorphisms (SNPs) have been reported for MDR1 gene (http://www.…”

Comprehensive Biochemical Analysis of Rare Prostacyclin Receptor Variants

“…Cells were fixed and permeabilized 48 h post-transfection in icecold methanol. Prostacyclin receptors were labeled using anti-1D4 monoclonal antibody (C-terminal tagged hIP) followed by goat anti-mouse IgG F(abЈ) 2 Alexa Fluor 568 fluorescent antibody (Molecular Probes, Inc.). The endoplasmic reticulum was labeled using anti-calnexin polyclonal antibody (Stressgen Bioreagents) followed by goat anti-rabbit IgG Alexa Fluor 488 fluorescent antibody (Molecular Probes, Inc.).…”

“…no change in amino acid sequence) or non-synonymous (change in amino acid sequence) mutations. They are implicated in the pathogenesis of diseases (1), in the efficacy of drugs, and in drug-to-drug interactions (2)(3)(4). It is now generally believed that greater than 80% of the observed variability between individuals is the result of genetic variants (5).…”