Functional Characterization of Liver Enhancers That Regulate Drug‐Associated Transporters View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-04

AUTHORS

MJ Kim, P Skewes‐Cox, H Fukushima, S Hesselson, SW Yee, LB Ramsey, L Nguyen, JL Eshragh, RA Castro, CC Wen, D Stryke, SJ Johns, TE Ferrin, P‐Y Kwok, MV Relling, KM Giacomini, DL Kroetz, N Ahituv

ABSTRACT

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five--located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1--exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response. More... »

PAGES

571-578

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/clpt.2010.353

DOI

http://dx.doi.org/10.1038/clpt.2010.353

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1047311871

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21368754


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