Scientific Publications by FDA Staff

Pharmacogenomics 2007 Jan;8(1):29-39

Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene.

Kimchi-Sarfaty C, Marple AH, Shinar S, Kimchi AM, Scavo D, Roma MI, Kim IW, Jones A, Arora M, Gribar J, Gurwitz D, Gottesman MM

Gottesman MM (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA US FDA, Rockville, MD 20857 USA NIH, Natl Ctr Bioinformat, Bethesda, MD 20892 USA Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, Natl Lab Genet Israeli Populat, Tel Aviv, IL-69978 Israel

Introduction: The human multidrug resistance gene ATP-binding cassette B1 (ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anticancer 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 that 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. Methods: In this study, 95 individuals representative of the entire ethnic make-up of the USA were compared with 101 individuals from an Ashkenazi-Jewish population. These individuals were analyzed by genomic sequencing and polymerase chain reaction, using restriction fragment length polymorphisms, to calculate their genotype frequencies. Results: A total of 25 SNPs were located in the exons of the ABCB1 gene. All of the polymorphisms identified were in parts of the ABCB1 gene product predicted to be intracellular, and 16 appear to be novel as compared with those listed by the National Center for Biotechnological Information. Frequencies of the 1236C-->T and 2677G-->T/A/C SNPs were similar for the US and Ashkenazi populations (64.2 and 60.4%, respectively for 1236C-->T [chi(2): 0.30; p T/A/C [chi(2): 1.49; p T (24.2% for the US population and 69.3% for the Ashkenazi population [chi(2): 39.927; p T plays a significant role in the ABCB1 gene. The haplotype and genotype analysis from these data may be used as a basis for studies on the relationship between ABCB1 genotypes and drug efficacy, drug toxicity, disease susceptibility or other phenotypes.