Membrane transporters in the SLC and ABC superfamilies are of enormous pharmacological importance, serving as critical determinants of drug disposition and response. Building on the extensive infrastructure established during the previous granting cycles, the proposed research will focus on transporters in the liver and kidney, which interact with virtually all known drugs in mediating drug disposition, response and toxicity. Through computationally driven functional studies and multiple clinical studies, the proposed research will test the hypothesis that genetic variants in membrane transporters contribute to variation in drug response. The functional genomic studies will have a major emphasis on variants in noncoding regions, expanding on our current efforts, which are focused largely on nonsynonymous variants. For these studies, we propose to: (a) functionally characterize variants within regulatory regions of transporter genes;(b) associate sequence variants with transporter expression levels in liver and kidney samples;and (c) develop predictive models for substrate-dependent effects of nonsynonymous variants. In addition to common variants, we will continue to study rare variants as our previous studies have demonstrated their functional importance. Three types of clinical studies will be performed: (a) genotype-driven hypothesis testing studies in SOPHIE, a unique cohort of healthy volunteers who have provided DNA and agreed to be called back for follow-up studies;(b) a large genomewide association study in African Americans of response to the anti-diabetic drug, metformin, a drug that interacts with multiple transporters;and (c) collaborative studies on clinical samples in which a custom-designed transporter-ADME SNP chip will be used to identify genetic variants in transporters that are determinants of toxicities and response to multiple drugs. Our project has recruited a world-class multidisciplinary research team with computational, experimental and clinical expertise, who will apply innovative methodologies including RNA-seq, Next-generation sequencing and multi-stage genomewide association analysis. Three research cores, bioinformatics, biostatistics and genomics, will provide support for these highly mechanistic and clinically important studies.
Variation in drug response is a major health problem with many individuals failing to achieve therapeutic response or experiencing adverse reactions to clinically used drugs. This research will advance our knowledge of the mechanisms responsible for variation in drug response through the discovery of genetic variants in membrane transporters that determine drug levels in body tissues and in the blood.
|Ryu, Ann H; Eckalbar, Walter L; Kreimer, Anat et al. (2017) Use antibiotics in cell culture with caution: genome-wide identification of antibiotic-induced changes in gene expression and regulation. Sci Rep 7:7533|
|Chhibber, A; French, C E; Yee, S W et al. (2017) Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines. Pharmacogenomics J 17:137-145|
|Stecula, Adrian; Schlessinger, Avner; Giacomini, Kathleen M et al. (2017) Human Concentrative Nucleoside Transporter 3 (hCNT3, SLC28A3) Forms a Cyclic Homotrimer. Biochemistry 56:3475-3483|
|Wu, Hsin-Fang; Hristeva, Nadya; Chang, Jae et al. (2017) Rosuvastatin Pharmacokinetics in Asian and White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions. J Pharm Sci 106:2751-2757|
|Wheeler, Heather E; Gamazon, Eric R; Frisina, Robert D et al. (2017) Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity. Clin Cancer Res 23:3325-3333|
|Sá, Ana Caroline C; Webb, Amy; Gong, Yan et al. (2017) Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics. Sci Rep 7:16068|
|Eclov, Rachel J; Kim, Mee J; Smith, Robin P et al. (2017) In Vivo Hepatic Enhancer Elements in the Human ABCG2 Locus. Drug Metab Dispos 45:208-215|
|Dujic, T; Zhou, K; Yee, S W et al. (2017) Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis. Clin Pharmacol Ther 101:763-772|
|Zhou, Kaixin; Yee, Sook Wah; Seiser, Eric L et al. (2016) Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet 48:1055-1059|
|Mitchel, Katrina; Theusch, Elizabeth; Cubitt, Celia et al. (2016) RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol. Circ Cardiovasc Genet 9:223-30|
Showing the most recent 10 out of 148 publications