Exploring the genomic basis of pharmacoresistance in epilepsy: an integrative analysis of large-scale gene expression profiling studies on brain tissue from epilepsy surgery

Abstract

Some patients with pharmacoresistant epilepsy undergo therapeutic resection of the epileptic focus. At least 12 large-scale microarray studies on brain tissue from epilepsy surgery have been published over the last 10 years, but they have failed to make a significant impact upon our understanding of pharmacoresistance, because (1) doubts have been raised about their reproducibility, (2) only a small number of the gene expression changes found in each microarray study have been independently validated and (3) the results of different studies have not been integrated to give a coherent picture of the genetic changes involved in epilepsy pharmacoresistance. To overcome these limitations, we (1) assessed the reproducibility of the microarray studies by calculating the overlap between lists of differentially regulated genes from pairs of microarray studies and determining if this was greater than would be expected by chance alone, (2) used an inter-study cross-validation technique to simultaneously verify the expression changes of large numbers of genes and (3) used the combined results of the different microarray studies to perform an integrative analysis based on enriched gene ontology terms, networks and pathways. Using this approach, we respectively (1) demonstrate that there are statistically significant overlaps between the gene expression changes in different publications, (2) verify the differential expression of 233 genes and (3) identify the biological processes, networks and genes likely to be most important in the development of pharmacoresistant epilepsy. Our analysis provides novel biologically plausible candidate genes and pathways which warrant further investigation to assess their causal relevance.

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

“…This could be explained by the fact that most AEDs do not seem to be substrates of ABCB1 [199,200] and that the impact of SNPs on ABCB1 expression in the bloodbrain barrier is only modest [201,202]. The observed overexpression of ABCB1 in epileptic brain tissue could, therefore, be just an epiphenomenon [203], suggesting the involvement of other genes [202,204,205].…”

Pharmacogenomics and the Resulting Impact on Psoriasis Therapies

“…Meta-analysis methods that integrate the results of separate genomic assessments are now being used to allow the identification of cellular components, biological processes, molecular functions, pathways, networks, and individual genes in diseases such as epilepsy. 63 This strategy could be used in psoriasis, in which sufficient comparable genomic data exist.…”

Genetic epilepsies. Remarks on the proposed “Organization of the Epilepsies”

“…These authors showed that for some epilepsy phenotypes it is becoming possible to predict the most efficacious antiepileptic drugs for patients based on their genetic makeup (Yamada et al, 2013;Sugawara et al, 2013). In a similar way pharmacoresistance can be determined by genetic studies (Mirza et al, 2011;Lachos et al, 2011). Thus, the development of individualized medicine is expected to greatly improve the management of epilepsy patients .…”