Mining Potential Functionally Significant Polymorphisms at the ATP-Binding- Cassette Transporter Genes

Z.      Wang; J.      Wang; S.   S.   Chong; C.   G.L.   Lee

Abstract

The ATP-Binding-Cassette (ABC) superfamily of transporters, implicated in the traffic of drugs/xenobiotics across membranes, represents one of the larger families of drug-response genes. Many of these transporters are expressed at apical membranes of barrier tissues where they offer protection against orally ingested or airborne toxins. They can also modulate the absorption of orally administered drugs to influence drug-disposition. Hence, genetic polymorphisms at these genes may account, in part, for inter-individual variation in drug-response. With the identification of an increasing number of polymorphisms even for individual genes, it has become increasingly difficult to associate polymorphisms at these gene loci with drug-response due to increased Type I error if all SNPs in these genes are examined. It is therefore worthwhile and timely to identify a subset of SNPs at the ABC gene loci that have potential functional significance to facilitate future association studies. In this review, we describe approaches that are being adopted to rationally select a subset of SNPs for association studies including the tagging-SNP strategy as well as strategies to identify SNPs of potential functional significance either through population-genetics, evolutionary or structural approaches. In addition, databases were mined to identify SNPs in the ABC gene loci that may have potential significance. Finally, the literature was also mined for SNPs at the ABC gene loci that were previously reported to be associated with drug-response or other phenotypes. The value of these SNPs in facilitating the ushering of the era of personalized medicine will be discussed.

Keywords: SNP, ABC transporter family, association study, drug response, functional polymorphism

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