Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation
| Autor: | Yuya Kobayashi, Benjamin Ma, Deanna L. Kroetz, Maarke J.E. Roelofs, Sook Wah Yee, Ji Ha Choi, Stephanie Hesselson, Ligong Chen, Connie Ha, Hisayo Fukushima, Pui-Yan Kwok, Harunobu Tahara, Kathleen M. Giacomini, Pär Matsson, Richard M. Myers, Nicolas Picard, James E. Shima, Doug Stryke, Susan J. Johns, Elin Sjödin, Annie Poon, Jason M. Gow, Richard A. Castro, Thomas E. Ferrin |
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| Přispěvatelé: | Zanger, Ulrich |
| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Adolescent General Science & Technology Genetics and Genomics/Pharmacogenomics lcsh:Medicine ATP-binding cassette transporter Single-nucleotide polymorphism Biology Kidney 030226 pharmacology & pharmacy Nucleotide diversity Promoter Regions 03 medical and health sciences 0302 clinical medicine Gene Frequency Genetic Genetics and Genomics/Population Genetics Genetics Humans Polymorphism Promoter Regions Genetic lcsh:Science Gene 030304 developmental biology 0303 health sciences Multidisciplinary Polymorphism Genetic lcsh:R Cell Membrane Kidney metabolism Genetic Variation Promoter Solute carrier family Pharmacology/Adverse Reactions Liver Gene Expression Regulation Multigene Family lcsh:Q ATP-Binding Cassette Transporters Female Efflux Pharmacology/Personalized Medicine Carrier Proteins Research Article |
| Zdroj: | PloS one, vol 4, iss 9 PLoS ONE, Vol 4, Iss 9, p e6942 (2009) PLoS ONE |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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