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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 with in vitro phenotyping 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 the OCT2 gene 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 in Xenopus laevis oocytes. Analysis of nucleotide diversity (pi) revealed a higher prevalence of synonymous (pi = 22.4 x 10-4) versus non-synonymous (pi = 2.1 x 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's D-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.
Leabman et al. (Mon,) studied this question.