title: Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation.
abstract: Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (pi) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Hesselson
authors.forename: Pär
authors.initials: P
authors.lastname: Matsson
authors.forename: James E
authors.initials: JE
authors.lastname: Shima
authors.forename: Hisayo
authors.initials: H
authors.lastname: Fukushima
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Jason M
authors.initials: JM
authors.lastname: Gow
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ma
authors.forename: Annie
authors.initials: A
authors.lastname: Poon
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Johns
authors.forename: Doug
authors.initials: D
authors.lastname: Stryke
authors.forename: Richard A
authors.initials: RA
authors.lastname: Castro
authors.forename: Harunobu
authors.initials: H
authors.lastname: Tahara
authors.forename: Ji Ha
authors.initials: JH
authors.lastname: Choi
authors.forename: Ligong
authors.initials: L
authors.lastname: Chen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.forename: Elin
authors.initials: E
authors.lastname: Sjödin
authors.forename: Maarke J E
authors.initials: MJ
authors.lastname: Roelofs
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Ferrin
authors.forename: Richard
authors.initials: R
authors.lastname: Myers
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D005810:Multigene Family; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
chemical_list: D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins