Pharmacogenomics genes show varying perceptibility to microRNA regulation

Abstract

The aim of pharmacogenomics is to identify individual differences in genome and transcriptome composition and their effect on drug efficacy. MicroRNAs (miRNAs) are short noncoding RNAs that negatively regulate expression of the majority of animal genes, including many genes involved in drug efficacy. Consequently, differences in the miRNA expression among individuals could be an important factor contributing to differential drug response. Pharmacogenomics genes can be divided into drug target genes termed as pharmacodynamics genes (PD) and genes involved in drug transport and metabolism termed as pharmacokinetics genes (PK). To clarify the regulatory potential of miRNAs in pharmacogenomics, we have examined the potential regulation by miRNAs of PK and PD genes. We identified PK and PD genes as annotated by the Pharmacogenomics Knowledge Base and examined miRNA targeting of genes in the two groups according to several miRNA target prediction databases. We furthermore studied how differences between the two groups are reflected in the gene structure and across gene families. Lastly, we studied changes in expression levels of PK versus PD genes in cells depleted for miRNAs by shRNA-mediated knockdown of the miRNA-processing enzyme Dicer. Our analysis identify a striking difference in the level of miRNA regulation between PK and PD genes, with the former having less than half predicted conserved miRNA binding sites compared with the latter. Importantly, this finding is reflected in a highly significant difference in the shift in expression levels of PD versus PK genes after depletion of miRNAs. Our study emphasizes an intrinsic difference between PK and PD genes and helps clarify the role of miRNAs in pharmacogenomics.