The pharmacogenomics of membrane transporters project: research at the interface of genomics and transporter pharmacology

Abstract

Since the cloning of the first membrane transporter, our understanding of the role of transporters in clinical drug disposition and response has grown enormously. In parallel, large-scale genome-wide variation studies and the emerging field of pharmacogenomics have ushered in a new understanding of variations in drug response. At the crossroads of pharmacogenomics and transporter biology is the National Institutes of Health-funded Pharmacogenomics of Membrane Transporters (PMT) project, centered at the University of California, San Francisco.

Figure 1

Overview of the Pharmacogenomics of Membrane Transporters (PMT) project and dbPMT. (a) Organizational structure of PMT. (b) Screen views of dbPMT showing a typical detailed PMT experiment report—in this instance, from a sequencing experiment of the organic-anion transporter gene, SLC22A8 (OAT3). The middle section shows the details of the experiment, including interrogated genomic range and genotype information on detected variants. The bottom panel shows the putative secondary structure of SLC22A8 (OAT3) and positions of the nonsynonymous variants (red circles) and synonymous variants (green circles). The transmembrane topology diagram was rendered using TOPO2 transmembrane display software (http://www.sacs.ucsf.edu/TOPO2/topo2.html). SLC, solute carrier superfamily.

Figure 1

Overview of the Pharmacogenomics of Membrane Transporters (PMT) project and dbPMT. (a) Organizational structure of PMT. (b) Screen views of dbPMT showing a typical detailed PMT experiment report—in this instance, from a sequencing experiment of the organic-anion transporter gene, SLC22A8 (OAT3). The middle section shows the details of the experiment, including interrogated genomic range and genotype information on detected variants. The bottom panel shows the putative secondary structure of SLC22A8 (OAT3) and positions of the nonsynonymous variants (red circles) and synonymous variants (green circles). The transmembrane topology diagram was rendered using TOPO2 transmembrane display software (http://www.sacs.ucsf.edu/TOPO2/topo2.html). SLC, solute carrier superfamily.

Figure 2

An overview of the scientific approaches used by PMT in SNP discovery and functional studies. The PMT SNP discovery studies involve resequencing of coding and noncoding regions of membrane transporter genes in healthy volunteers in four major ethnic groups (the SOPHIE cohort). Various in vitro and in vivo assays are used to characterize coding and noncoding region variants in transporters. In order to validate functional findings and to translate them from bench to clinic, one or more of the following scenarios are applicable. (i) Hypothesis-driven clinical studies to evaluate the role of functionally important genetic variants in drug disposition and response in the SOPHIE cohort (figure from scenario 1 reprinted from ref. 8). (ii) and (iii) Collaborative clinical studies involving PGRN investigators, CALGB, and GAP-J, with a focus on the role of genetic variants in transporters in drug response and toxicity. (iv) Association of functional SNPs with expression levels of transporters in liver and kidney samples. ABC, ATP-binding cassette; CALGB, Cancer and Leukemia Group B; GAP-J, Global Alliance in Pharmacogenomics, Japan; PGRN, Pharmacogenetics Research Network; PMT, Pharmacogenomics of Membrane Transporters project; SLC, solute carrier superfamily; SNP, single-nucleotide polymorphism; SOPHIE, Study of Pharmacogenetics in Ethnically Diverse Populations.