Received for publication December 8, 2005.
Revised June 7, 2006.
Accepted for publication June 7, 2006.

GENETIC VARIABILITY, HAPLOTYPE STRUCTURES, AND ETHNICAL DIVERSITY OF HEPATIC TRANSPORTERS MDR3 (ABCB4) AND BSEP (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 (BSEP, ABCB11). Mutations in the ABCB4 and ABCB11 contribute to cholestatic diseases (e.g. PFIC2, PFIC3 and ICP) and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy population of different ethnic background. All coding exons, 5 of 6 non-coding exons, 50-300 bp of the flanking intronic regions and 2.5-2.8 kb of the promoter regions of ABCB4 and ABCB11, were sequenced in 159 and 196 DNA samples of Caucasian, African American, Japanese and Korean origin. Totally, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively, among them 14 and 28 exonic polymorphisms, 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 in 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 to 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 in future research on the hereditary of cholestatic liver injury.

Key words: ABC transporters, ethnic differences, hepatobiliary transport, hepatotoxicity, human genetics, liver disease, liver injury, pharmacogenetics, pharmacogenomics, transporters

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