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Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms
Author(s) -
Poonkuzhali B.,
Lamba J.,
Strom S.,
Sparreboom S.,
Thummel K.,
Watkins P.,
Schuetz E.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.372.2
Subject(s) - single nucleotide polymorphism , biology , abcg2 , exon , microbiology and biotechnology , genotype , promoter , intron , genetics , allele , dbsnp , snp , gene , gene expression , atp binding cassette transporter , transporter
The hypothesis was tested that sequence diversity in breast cancer resistance protein (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 single nucleotide polymorphisms (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 p.o. imatinib. Liver polymorphically expressed an alternatively spliced mRNA [splice variant (SV) 1] skipping exon 2. Although SV1+ livers did not uniformly carry the exon 2 G34A allele, 90% of G34A livers expressed SV1. BCRP mRNA was significantly lower among Hispanic livers with the G34A variant genotype and may be due, in part, to polymorphic exon 2 splicing. Allele expression imbalance and use of multiple promoters were seen in BCRP mRNA. In conclusion, BCRP expression in lymphoblasts, liver, and intestine is associated with novel promoter and intron 1 SNPs.