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Drug Metabolism and Disposition Fast Forward
First published on January 7, 2008; DOI: 10.1124/dmd.107.018366

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Received for publication August 17, 2007.
Revised December 24, 2007.
Accepted for publication January 3, 2008.

Association of BCRP/ABCG2 Phenotypes with Novel promoter and intron1 SNPs

Balasubramanian Poonkuzhali 1, Jatinder Lamba 2, Stephen Strom 3, Alex Sparreboom 2, Kenneth Thummel 4, Paul B Watkins 5, Erin G. Schuetz 2*

1 University of Chicago 2 St Jude Children's Research Hospital 3 University of Pittsburgh 4 University of Washington 5 University of North Carolina

* Address correspondence to: E-mail: erin.schuetz{at}stjude.org

Abstract

The hypothesis was tested that sequence diversity in BCRP's cis-regulatory region is a significant determinant of BCRP expression. The BCRP promoter and intron 1 were resequenced in lymphoblast DNA from the polymorphism discovery resource (PDR) 44 subset. BCRP SNPs were genotyped in donor human livers, intestines and lymphoblasts quantitatively phenotyped for BCRP mRNA expression. Carriers of the -15622C>T SNP had lower BCRP expression in multiple tissues. The intron 1 SNP 16702C>T was associated with high expression in livers; 1143G>A was associated with low expression in intestine; 12283T>C was associated with higher expression in the PDR44 and White livers. The -15994C>T promoter SNP was significantly associated with higher BCRP expression in multiple tissues. Patients with the -15994C>T genotype had substantially higher clearance of oral imatinib. We next determined if BCRP expression was related to polymorphic alternative splicing or alternative promoter use. Liver polymorphically expressed an alternatively spliced mRNA (SV1) skipping exon 2. Although SV1+ livers did not uniformly carry the ex2 G34A allele, 90% of G34A livers expressed SV1 (vs. 4% of 34GG livers) and BCRP mRNA was significantly lower among Hispanic livers with the G34A variant genotype. Analysis of allele expression imbalance (AEI) showed that PDR44 samples with AEI had lower BCRP mRNA expression, however, no linked cis-polymorphisms were identified. BCRP utilized multiple promoters, and livers differentially using alternative exon 1b had lower BCRP. Conclusion: BCRP expression in lymphoblasts, liver and intestine is associated with novel promoter and intron 1 SNPs.


Key words: ABC transporters, pharmacogenetics


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