PMT Abstract, 2003

Pharmacogenetics of Membrane Transporters

Goals

The Pharmacogenetics of Membrane Transporters project is a comprehensive research program in which investigators from diverse disciplines conduct integrated studies to elucidate the pharmacogenetics of membrane transporters. This class of proteins is of great pharmacological importance as it provides the target for about 20% of the most commonly used prescription drugs and is a major determinant of pharmacokinetics. We seek to identify sequence variants in a large number of transporter genes with known or suspected relevance to pharmacogenetics. These transporters represent two major functional groups: those that govern pharmacokinetics and those that transport neurotransmitters and are from two large superfamilies of proteins: ATP Binding Cassette (ABC) Superfamily and Solute Carrier Superfamily (SLC).

• The first aim of our project is to identify natural variants of membrane transporter genes in ethnically diverse populations. Variants are identified in DNA samples from African Americans, European Americans, Asian Americans and Mexican Americans. Sequence variants and frequency information are deposited in PharmGKB. Haplotypes are identified for each transporter gene in the ethnic populations.
• The second aim of the project is to functionally characterize variants at a cellular level. Variants are constructed using site-directed mutagenesis and the interaction kinetics of the variant transporters with drugs and other xenobiotics are evaluated in heterologous expression systems including oocytes, yeast and mammalian cells. Studies focus particularly on non-synonymous variants.
• The third aim of the project is to determine the clinical significance of selected transporter variants by testing the hypothesis that variations in these genes are responsible for interindividual differences in drug response. We have two lead clinical studies. The Genetics of Response to Anti-Depressants (GRAD) uses the diverse patient population of Northern California Kaiser Permanente to test the hypothesis that variants in neurotransmitter transporters are associated with altered response to anti-depressants. Our second lead clinical study is Studies of Pharmacogenetics in Ethnically Diverse Populations (SOPHIE), an ethnically diverse cohort of healthy volunteers who have donated DNA for pharmacogenetic studies. These individuals have agreed to be called back for follow-up pharmacogenetic studies. Current studies of SOPHIE include evaluating the pharmacokinetics of model drugs in individuals with particular transporter genotypes.

Progress

PMT has identified variants in the coding region of 24 membrane transporter genes in ethnically diverse population samples and is in the process of identifying variants in ca. 20 more transporter genes. Comprehensive functional screens of in heterologous expression systems have been performed for ca. 80 to 90 variants in 12 membrane transporter genes. GRAD has enrolled 1000 individuals diagnosed with depression and treated with an SSRI anti-depressant. We are in the process of selecting candidate drug response genes, including membrane transporters, to screen for association with responses and adverse drug reactions to anti-depressants. SOPHIE has enrolled ca. 600 individuals who have all agreed to be called for further pharmacogenetic studies. To date, all of the variant data in 24 membrane transporters has been deposited in PHARMGKB. Cellular phenotypic data for some of the variants have also been deposited.