Pediatric pharmacogenetic and pharmacogenomic studies: the current state and future perspectives

Abstract

Genetic differences between individuals can explain some of the variability observed during drug treatment. Many studies have correlated the different pharmacological response to genetic variability, but most of them have been conducted on adult populations. Much less attention has been given to pediatric population. Pediatric patients constitute a vulnerable group with regard to rational drug prescribing since they present differences arising from the various stage of development. However, only few steps have been made in developmental pharmacogenomics. This review attempts to describe the current methods for pharmacogenetic and pharmacogenomic studies, providing some of the most studied examples in pediatric patients. It also gives an overview on the implication and importance of microRNA polymorphisms, transcriptomics, metabonomics and proteomics in pharmacogenetics and pharmacogenomics studies.

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

“…This approach examines the active treatment arm of a clinical trial and divides subjects into two groups: those with positive response and those with negative or no response. The groups are then genotyped for a particular candidate gene considered to be related to the treatment phenotype (Russo et al, 2011). These types of studies are easy to perform, but they also present a number of potential biases or difficulties in interpretation.…”

“…It is therefore necessary to ensure a good match between the genetic background of cases and controls to avoid biased sampling; techniques that can be employed to detect or eliminate the potential bias of population stratification are the match of cases and controls for ethnicity or the use of multiple unlinked markers (Pritchard & Rosenberg, 1999). Moreover, it is also indispensable to consider additional aspects such as sample size (Campbell et al, 1995), replication selection of candidate gene polymorphism (bioinformatic tools), observation bias (phenotyping and genotyping methods), linkage disequilibrium, allele or genotyped analysis, multivariate analysis, gene-gene and geneenvironment interaction, and correction for multiple comparisons to guarantee the quality of the study and preventing false positive associations (Russo et al, 2011). Efficient and powerful tools to identify inherited DNA sequence variations that contribute to phenotypic expression and variability are available to geneticists thanks to very high throughput DNA analysis technologies (e.g., single nucleotide polymorphism [SNP] array) and databases (HapMap project) harboring information about the genomic positions of DNA sequence variations.…”

“…In fact, it is now possible to test a great amount of polymorphic markers for association with a particular phenotype in a single study, the genome-wide association study (GWAS). GWASs are an important approach for revealing polymorphisms accounting for individual differences in drug efficacy and drug safety (Gurwitz & McLeod, 2009), as shown by Crowley et al and by the NHGRI GWAS catalog that summarized the results of 12 published pharmacogenomics GWASs (Crowley et al, 2009;National Human Genome Research Institute, n.d.) and showed that 6 of these GWASs evaluated the association of genetic variation with drug efficacy, five assessed adverse effects, and one examined a doseresponse relationship (Russo et al, 2011). Despite their efficiency and potential for leading to useful clinical medicine and public health applications, however, genome-wide association studies have been used in only two drug clinical trials so far, each nonetheless providing relevant insights for future research (Russo et al, 2011, Maitland et al, 2007.…”

“…GWASs are an important approach for revealing polymorphisms accounting for individual differences in drug efficacy and drug safety (Gurwitz & McLeod, 2009), as shown by Crowley et al and by the NHGRI GWAS catalog that summarized the results of 12 published pharmacogenomics GWASs (Crowley et al, 2009;National Human Genome Research Institute, n.d.) and showed that 6 of these GWASs evaluated the association of genetic variation with drug efficacy, five assessed adverse effects, and one examined a doseresponse relationship (Russo et al, 2011). Despite their efficiency and potential for leading to useful clinical medicine and public health applications, however, genome-wide association studies have been used in only two drug clinical trials so far, each nonetheless providing relevant insights for future research (Russo et al, 2011, Maitland et al, 2007. A new and promising field of research is pharmacogenomics of miRNA (Lagos-Quintana et al, 2001;Lau et al, 2001;Lee & Ambros, 2001), defined as the study of microRNAs and polymorphisms affecting miRNA function with the aim to predict drug behaviour and improve drug efficiency (Mishra et al, 2008;Mishra & Bertino, 2009).…”

“…MiRNAs, small, single-stranded, 21-23 nucleotide-long, independent functional units of noncoding RNA, are drug targets that regulate expression of several important proteins in the cell and are differentially expressed in malignant versus normal cells, thus providing MiRNA pharmacogenomics with strong clinical implications (Mishra et al, 2007;Calin et al, 2002;Hon & Zhang, 2007;Iorio et al, 2005). MiR-polymorphisms, in fact, have the potential to be employed predictors of drug response and may lead to the development of more accurate methods of determining appropriate drug dosage based on a patient's genetic makeup, thus decreasing the likelihood of drug overdose (Russo et al, 2011;Mishra & Bertino, 2009). …”