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Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance

Leschziner, Guya b; Zabaneh, Delilaha; Pirmohamed, M.c; Owen, Andrewc; Rogers, Janeb; Coffey, Alison J.b; Balding, David J.a; Bentley, David B.b; Johnson, Michael R.a

Pharmacogenetics and Genomics: June 2006 - Volume 16 - Issue 6 - p 439-450
doi: 10.1097/01.fpc.0000197467.21964.67
ORIGINAL ARTICLES
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Background The ATP-binding cassette (ABC) proteins are a superfamily of efflux pumps implicated as a mechanism for multidrug resistance in cytotoxic chemotherapy, immunosuppressive therapy, HIV and epilepsy. Genetic variation in P-glycoprotein, the product of the ABCB1 gene, is proposed to mediate de novo drug resistance, but associations between polymorphisms in ABCB1 and pharmacoresistance have produced conflicting results. Potential explanations for the inconsistency of results include inadequate characterization of gene structure, variation and linkage disequilibrium (LD) in ABCB1, as well as overlap in substrate specificity between ABCB1 and the various other drug transporters.

Methods and results We undertook a fundamental analysis of gene structure, variation and LD in ABCB1 and four other drug transporter genes implicated in pharmacoresistance: ABCC1, ABCC2, ABCC5 and ABCB4. Manual annotation of the five genes revealed nine shorter alternative transcripts with new untranslated regions and one novel region of coding sequence, demonstrating that on-line annotations are incomplete. Sequencing of exons in 47 Caucasian individuals identified 75 novel single nucleotide polymorphisms (SNPs) previously undescribed in any public database, including 14 new coding sequence SNPs. Genotyping of 502 SNPs in 842 Caucasian individuals across the five genes revealed large blocks of high LD, and low haplotype diversity across all five genes that could be characterized by between 67 and 114 tagging SNPs, depending on the tagging criteria.

Conclusion The study illustrates that publicly available data resources on genomic organization of genes and common variation can have important gaps and limitations, and establishes a comprehensive set of tagging SNPs for future association studies in pharmacoresistance.

aImperial College, London, UK

bWellcome Trust Sanger Institute, Cambridge, UK

cUniversity of Liverpool, Liverpool, UK

Correspondence and requests for reprints to Dr M. R. Johnson, Division of Neurosciences, Imperial College London, Room 10E07, Charing Cross Hospital, London W6 8RF, UK

Tel: +44 208 846 1194; fax: +44 208 846 7204;

e-mail: m.johnson@imperial.ac.uk

Received 4 October 2005; Accepted 13 December 2005

© 2006 Lippincott Williams & Wilkins, Inc.