Identification and functional assessment of BCRP polymorphisms in a Korean population.
The breast cancer resistance protein (BCRP) is a member of the ATP-binding cassette transporters. The aim of the present study was to identify genetic variants of BCRP in Koreans and to assess the functional consequences of BCRP polymorphisms. Twenty single nucleotide polymorphisms (SNP), including four nonsynonymous SNP, were identified by DNA sequencing of the BCRP gene in 92 Korean subjects. BCRP V12M, Q141K, P269S, and Q126Stop were detected at frequencies of 23, 28, 0.2, and 1.9%, respectively. These four coding variants were also screened in Chinese and Vietnamese subjects; the allelic frequencies among the three populations were compared; and predictions were made as to the potential frequency of each variant. In vitro functional analyses of the P269S protein and the promoter SNP -19031C>T (mutated in the hypoxia-inducible factor-1alpha binding site) were performed and compared with those of the wild type. P269S exhibited a 35 to 40% decrease in vesicular uptake of [(3)H]estrone-3-sulfate and [(3)H]methotrexate compared with the wild type. The promoter SNP -19031C>T did not affect BCRP promoter activity in either the presence or absence of chemical-induced hypoxic stress. Our results suggest that the P269S variant could be a functionally altered variant. Genotyping of this variant in clinical studies is needed to address its phenotypic role. Genetic polymorphisms of BCRP were found to be very common in Koreans, as well as in other ethnic groups. Comparative analyses among three Asian populations revealed different frequencies for the four functional BCRP variants.
Lee
Sang Seop
SS
Department of Pharmacology, Pharmacogenomics Research Center, College of Medicine, Inje University, 633-165 Gaegum-Dong, Jin-Gu, Busan 614-735, Korea. phshinjg@inje.ac.kr
Jeong
Hye-Eun
HE
Yi
Joo-Mi
JM
Jung
Hyun-Ju
HJ
Jang
Jae-Eun
JE
Kim
Eun-Young
EY
Lee
Su-Jun
SJ
Shin
Jae-Gook
JG
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D044466:Asian People / Q000235:genetics*; D002460:Cell Line; D002681:China; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D066298:In Vitro Techniques; D007313:Insecta; D007723:Korea; D008727:Methotrexate / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014744:Vietnam
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D004970:Estrone; D000251:Adenosine Triphosphatases; C017296:estrone sulfate; D008727:Methotrexate