title: Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).
abstract: Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.
authors.affiliation: EPIDAUROS Biotechnologie AG, Bernried, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lang
authors.forename: Michael
authors.initials: M
authors.lastname: Haberl
authors.forename: Diana
authors.initials: D
authors.lastname: Jung
authors.forename: Anja
authors.initials: A
authors.lastname: Drescher
authors.forename: Robert
authors.initials: R
authors.lastname: Schlagenhaufer
authors.forename: Andrea
authors.initials: A
authors.lastname: Keil
authors.forename: Esther
authors.initials: E
authors.lastname: Mornhinweg
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kerb
mesh_terms: D024506:5' Flanking Region / Q000235:genetics; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001741:Black or African American / Q000235:genetics*; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001647:Bile Acids and Salts / Q000378:metabolism; D045744:Cell Line, Tumor; D002779:Cholestasis / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D017930:Genes, Reporter; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D008156:Luciferases; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D014162:Transfection; D044465:White People / Q000235:genetics*
chemical_list: C093491:ABCB11 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; C095122:multidrug resistance protein 3; D008156:Luciferases