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PMT Profile

Pharmacogenetics of Membrane Transporters

Website

http://pharmacogenetics.ucsf.edu/

Principal Investigator

Kathleen M. Giacomini, PhD

Host Institution

University of California, San Francisco

Grant Number

2U19GM061390-11

PGRN 2010 Retreat Poster

PMT Poster

Publications

PMT Publications

TOP Publications PMT Publications

Abstract (Updated, May 2013)

Goals

The major goal of the Pharmacogenomics of Membrane Transporters (PMT) group is to develop a comprehensive functional map of genetic variants in ATP Binding Cassette (ABC) and SoLute Carrier (SLC) membrane transporters superfamilies and to identify variants in membrane transporters that contribute to variation in drug response.

Progress

In this funding cycle, we have focused on mechanistic studies in cells and in tissues to functionally characterize genetic variations in membrane transporters. Our chief findings are that MATE1 and MATE2 promoter variants contribute to variation in disposition and response to the anti-diabetic drug, metformin, which is now among the world¿s most widely prescribed drugs. Differences in response to metformin between Asian, African Americans and Caucasians have been observed, suggesting that genetic variants may underlie ethnic specific differences in response to metformin. In addition, we have also identified functional variants in the ABCC2 promoter region. Using evolutionary conservation method, we identified regulatory regions of ABCG2 and performed mechanistic studies in cells and tissues. Wide range of prescriptions drugs are known to interact with the ABC transporters and thus understanding the functional variants in these transporters will contribute our understanding of these variants in drug dispositions and response.

Other key studies include the development of structural models of membrane transporters such as the Large Neutral Amino Acid transporter, LAT1, nucleoside transporters, CNTs, and transporters for ¿-Aminobutyric acid, GABA, and virtual docking of prescription drug libraries to ascertain potential substrates and inhibitors of the transporters. We are also continuing our hypothesis generating genotype-to-phenotype studies in healthy volunteers from multiple ethnic groups to support the above mechanistic studies. These studies have provided a foundation for studies of genetic variation in clinical drug response. Our clinical studies of genetics of response to metformin in African Americans are well underway. Through the funding of PGRN-RIKEN CGM Network Resource, PMT has actively participated in contributing different clinical samples for pharmacogenomics studies on drug response and drug toxicity related to anti-cancer, anti-viral and anti-diabetes drugs. We continue data analyses of the genomewide association studies

Experimental Plans

We will expand our multidisciplinary research project to integrate computational and mechanistic studies in cells, animal models and in ethnically diverse human populations. We will continue to focus on determining the role of genetic variants in membrane transporters in the liver and kidney that play a role in drug disposition and response. Our clinical studies will include genotype to phenotype proof of concept studies and large collaborative clinical studies. In addition, we will accrue samples from about 2000 individuals with type 2 diabetes on metformin and identify, using genomewide approaches, variants that contribute to response and adverse response. These studies will take a mechanistic approach with the goal of identifying causal variants that can provide information to enhance drug therapy. Ultimately, our studies will contribute to the development of personalized therapies.

Research Team

Functional Genomics
Nadav Ahituv, PhD
Co-Investigator
Email: nadav.ahituv@ucsf.edu
Phone: (415) 476-1936
Leslie Z Benet, PhD
Co-Investigator
Email: benet@itsa.ucsf.edu
Phone: (415) 476-3853
Deanna L. Kroetz, PhD
Co-Director, Cellular Phenotyping
Email: deanna.kroetz@ucsf.edu
Phone: (415) 476-1159
Kathleen M. Giacomini, PhD
Principal Investigator
Email: kathy.giacomini@ucsf.edu
Phone: (415) 476-1936
Hobart Harris M.D., MPH
Co-Investigator
Email: Hobart.Harris@ucsfmedctr.org
Xin Chen, PhD
Co-Investigator
Email: chenx@pharmacy.ucsf.edu
Phone: (415) 502-6526
 
 
Computational Genomics
Andrej Sali, PhD
Co-Investigator
Email: sali@salilab.org
Phone: (415) 476-4227
Steve Brenner, PhD
Co-Investigator
Email: brenner@compbio.berkeley.edu
Phone: (510) 643-9131
Hao Li, PhD
Co-Investigator
Email: haoli@genome.ucsf.edu
Phone: (415) 502-8187
 
Clinical Studies
Esteban Gonzalez Burchard, MD
SOPHIE Core Director
Email: eburch@itsa.ucsf.edu
Phone: (415) 206-3491
Claire Brett, MD
Collaborative Core Director
Email: brettc@anesthesia.ucsf.edu
Phone: (415) 476-9694
Richard Castro, MD
PMT/Clinical Director
Email: castror@pharmacy.ucsf.edu
Phone: (415) 476-1840
Kathleen M. Giacomini, PhD
Principal Investigator
Email: kathy.giacomini@ucsf.edu
Phone: (415) 476-1936
Deanna L. Kroetz, PhD
Co-Director, Cellular Phenotyping
Email: deanna.kroetz@ucsf.edu
Phone: (415) 476-1159
Howard Lee MD, PhD
Consultant
Email: Howard.Lee@ucsf.edu
Clinical Studies-Metformin
Kathleen M. Giacomini, PhD
Principal Investigator
Email: kathy.giacomini@ucsf.edu
Phone: (415) 476-1936
Robert L. Davis, M.D., MPH
Co-Investigator
Email: Robert.L.Davis@kp.org
Phone: (404) 364-7197
Monique Hedderson, PhD, MPH
Co-Investigator
Email: Monique.M.Hedderson@nsmtp.kp.org
Phone: (510) 891-3580
Kristi D. Silver, MD
Co-Investigator
Email: Ksilver@medicine.umaryland.edu Phone: (410) 706-1628
Genomics Core
Pui Kwok, MD, PhD
Genomics Core Director
Email: kwok@itsa.ucsf.edu
Phone: (415) 514-3802
 
 
 
Biostatistics Core
John Witte, PhD
Statistical Core Director
Email: jwitte@itsa.ucsf.edu
Phone: (415) 502-6882
Neil Risch, PhD
Co-Investigator
Email: rischn@humgen.ucsf.edu
Phone: (415) 476-1127
 
 
Bioinformatics Core
Thomas E. Ferrin, PhD
Director, Bioinformatics Core
Email: tef@cgl.ucsf.edu
Phone: (415) 476-2299