Original ArticlesPolymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered functionLeabman, Maya K.; Huang, Conrad C.; Kawamoto, Michiko; Johns, Susan J.; Stryke, Douglas; Ferrin, Thomas E.; DeYoung, Joseph; Taylor, Travis; Clark, Andrew G.; Herskowitz, Ira; Giacomini, Kathleen M. on behalf of the Pharmacogenetics of Membrane Transporters InvestigatorsAuthor Information aDepartment of Biopharmaceutical Sciences, bDepartment of Pharmaceutical Chemistry, cGenomics Core Facility, Program in Human Genetics, dDepartment of Biochemistry and Biophysics and eProgram in Human Genetics, University of California, San Francisco, San Francisco, CA and fInstitute of Molecular Evolutionary Genetics, Department of Biology, Pennsylvania State University, University Park, PA USA Correspondence to Kathleen M. Giacomini, Department of Biopharmaceutical Sciences, University of California, San Francisco, 513 Parnassus Avenue, S-926, San Francisco, CA 94143-0446, USA Tel: +1 415 476 1936; fax: +1 415 502 4322; e-mail: [email protected] Received 12 February 2002 Accepted 4 April 2002 Pharmacogenetics: July 2002 - Volume 12 - Issue 5 - p 395-405 Buy Abstract The completion of the Human Genome Project and the development of high-throughput polymorphism identification methods have allowed researchers to carry out full genetic analyses of many clinically relevant genes. However, few studies have combined genetic analysis within vitrophenotyping to better understand the relationship between genetic variation and protein function. Many transporters in the kidney are thought to play key roles in defense against a variety of foreign substances. The goal of this study was to understand the relationship between variation in a gene encoding a major renal xenobiotic transporter, OCT2, and transporter function. We report a comprehensive genetic analysis and functional characterization of variants of OCT2. Twenty-eight variable sites in theOCT2gene were identified in a collection of 247 ethnically diverse DNA samples. Eight caused non-synonymous amino acid changes, of which four were present at >= 1% in an ethnic population. All four of these altered transporter function assayed inXenopus laevisoocytes. Analysis of nucleotide diversity (π) revealed a higher prevalence of synonymous (π = 22.4 × 10-4) versus non-synonymous (π = 2.1 × 10-4) changes in OCT2 than in other genes. In addition, the non-synonymous sites had a significant tendency to exhibit more skewed allele frequencies (more negative Tajima'sD- values) compared to synonymous sites. The population-genetic analysis, together with the functional characterization, suggests that selection has acted against amino acid changes in OCT2. This selection may be due to a necessary role of OCT2 in the renal elimination of endogenous amines or xenobiotics, including environmental toxins, neurotoxic amines and therapeutic drugs. © 2002 Lippincott Williams & Wilkins, Inc.