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Network Analysis of Gene Expression in Peripheral Blood Identifies Mtor and NF-&Kappa

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Network Analysis of Gene Expression in Peripheral Blood Identifies Mtor and NF-&Kappa The Pharmacogenomics Journal (2015) 15, 452–460 © 2015 Macmillan Publishers Limited All rights reserved 1470-269X/15 www.nature.com/tpj ORIGINAL ARTICLE Network analysis of gene expression in peripheral blood identifies mTOR and NF-κB pathways involved in antipsychotic-induced extrapyramidal symptoms S Mas1,2,3, P Gassó1,2, E Parellada1,2,3,4, M Bernardo2,3,4,5 and A Lafuente1,2,3 To identify the candidate genes for pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we propose a systems biology analytical approach, based on protein–protein interaction network construction and functional annotation analysis, of changes in gene expression (Human Genome U219 Array Plate) induced by treatment with risperidone or paliperidone in peripheral blood. 12 AP-naïve patients with first-episode psychosis participated in the present study. Our analysis revealed that, in response to AP treatment, constructed networks were enriched for different biological processes in patients without EPS (ubiquitination, protein folding and adenosine triphosphate (ATP) metabolism) compared with those presenting EPS (insulin receptor signaling, lipid modification, regulation of autophagy and immune response). Moreover, the observed differences also involved specific pathways, such as anaphase promoting complex /cdc20, prefoldin/CCT/triC and ATP synthesis in no-EPS patients, and mammalian target of rapamycin and NF-κB kinases in patients with EPS. Our results showing different patterns of gene expression in EPS patients, offer new and valuable markers for pharmacogenetic studies. The Pharmacogenomics Journal (2015) 15, 452–460; doi:10.1038/tpj.2014.84; published online 27 January 2015 INTRODUCTION intermediate phenotype that is regulated by a combination of 8 Because patients with schizophrenia differ substantially in terms of genetic, epigenetic and environmental factors. Several authors the side effects they experience, the severity of such effects, and have documented the potential utility of blood-based transcrip- also in their clinical response, treatment with antipsychotics (AP) tomic profiling as a source of biomarkers for schizophrenia. needs to be individually tailored to each patient. Genetic factors Although acknowledging that the blood-based approach might are generally assumed to contribute to variable treatment share some of the disadvantages inherent to the use of post- response, and this has led to a number of pharmacogenetic mortem brain tissue, as well as the fact that gene expression is studies being performed. Although treatment response has been only moderately correlated between the two sample types, several observed to correlate with a number of genetic variants, such as authors have reported that blood could act as a ‘surrogate’ for 9 dopamine D2 and D3 receptor variants1,2, there are as yet no underlying pathophysiology in psychiatric disorders. Moreover, definitive predictors of response.3 peripheral blood cells synthesize and express dopamine and also Pharmacogenetics has been driven by a candidate gene serotonin receptors and transporters on their plasma membrane, approach.4 The disadvantage of this approach is that the objects suggesting that they may constitute a cellular tool with which to of study are circumscribed by our current understanding of the monitor the effects of pharmacological treatments.10,11 Although mechanisms by which drugs act, and therefore this method gene association and expression studies have implicated many cannot identify hitherto unsuspected predictor genes. Apart from genes in the pharmacological effect of AP, most results have not their receptor-binding profile, little is known about the underlying been replicated or supported by the meta-analysis. Therefore, one molecular mechanism by which AP act. Since inhibition of research avenue involves the search for dysregulated molecular dopamine D2 receptors (which has been correlated with AP pathways. The advantage of this type of approach is that it has the efficacy and side effects such as extrapyramidal symptoms (EPS)) potential to reconcile poor biomarker reproducibility across should be achieved instantaneously, the beneficial therapeutic studies by identifying common biological pathways or functional effect cannot be limited to a straightforward interaction between modules.12 Moreover, in addition to the success of these methods such receptors and the drug. for the biological interpretation of genomic data, information is One approach that could help to elucidate the molecular also now available on relationships between gene products, signatures of AP treatments involves integrating pharmacoge- especially protein–protein interactions (PPI), and this can be used nomic data with other sources of data, for example, from the to define other types of modules. The use of the interactome studies of gene expression.5–7 Gene expression can bridge the gap allows the identification of sub-networks of interacting proteins between genetic variation and side effect susceptibility as an associated with genomic experiments, and these sub-networks 1Department Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain; 2Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 3Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain; 4Clinic Schizophrenia program, Psychiatry service, Hospital Clínic de Barcelona, Barcelona, Spain and 5Department Psychiatry and Clinical Psychobiology, University of Barcelona, Barcelona, Spain. Correspondence: Dr A Lafuente, Department Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, IDIBAPS, CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental, Spanish Ministry of Health, Instituto Carlos III), Casanova 143, Barcelona E-08036, Spain. E-mail: [email protected] Received 9 July 2014; revised 22 September 2014; accepted 5 November 2014; published online 27 January 2015 mTOR and NF-κB as candidate genes for AP-induced EPS S Mas et al 453 can be considered functional modules.13 Therefore, gene net- Table 1. Demographic and pharmacological characteristics of study works inferred from genomic data could be considered a higher participants level of structural functional modules operating in the cell. Here, we propose a systems biology analytical approach, based All Patients not Patients on PPI network construction and functional annotation analysis, of presenting presenting changes in gene expression induced by treatment with risper- EPS EPS fi idone or paliperidone in peripheral blood of drug-naive rst N1266 psychotic-episode schizophrenia patients, to examine the relation- Gender (male/female) 6/6 3/3 3/3 ship between these changes and the appearance of EPS. Identified Age (years ± s.d.) 26.08 ± 3.96 26.33 ± 4.27 25.83 ± 4.02 functional modules will provide potential candidate genes for Tobacco use N (%) 8 (66.66) 4 (66.66) 4 (66.66) Cannabis use N (%) 6 (50.00) 3 (50.00) 3 (50.00) future pharmacogenetic studies. Cocaine use N (%) 1 (8.33) 0 (0.00) 1 (16.6) Antipsychotic MATERIALS AND METHODS Risperidone (N) 633 Dosage (mg day − 1 ± s.d.) 5.83 ± 0.44 5.66 ± 0.57 6.00 ± 0.00 Subjects Paliperidone (N) 633 For the present study, we recruited 18 AP-naïve patients with first-episode Dosage (mg day − 1 ± s.d.) 12.85 ± 2.85 13.00 ± 4.58 12.75 ± 1.50 psychosis, all of them treated with risperidone or paliperidone (the active metabolite of risperidone). Subjects were diagnosed according to DSM-IV Abbreviation: EPS, extrapyramidal symptoms. criteria. For each patient two blood samples were collected in PAXgene Blood RNA tubes (PreAnalytiX Gmbh, Hombrechtikon, Switzerland); one upon admission to the psychiatric unit (prior to the initiation of AP treatment), (untreated status), and a second after 9 days (±1 day) of discovery rate. We also calculated the gene expression fold change. The continuous treatment with risperidone or paliperidone (treated status), or different comparisons made are summarized in Figure 1. as soon as any EPS appeared and prior to starting treatment with anti- parkinsonian drugs. No other concomitant treatments were administered during this time. All the participants were living in Catalonia at the time of PPI Network construction and evaluation the study, and only Caucasians were included. This ethnicity was Genes showing differential expression in response to AP treat- determined by self-reported ancestries; patients reported the ethnicity of ment were used (false discovery rate corrected P-value o0.01, fold each grandparent and we excluded subjects who mentioned non-European change42). The SNOW program, implemented in the Babelomics 4.3 suite, ancestry. Written informed consent was obtained from each subject. The was used for the analysis. SNOW contains a database of PPI from different 14 study was approved by the Ethics Committee of the Hospital Clínic. public repositories, and these were used to generate an interactome. Acute EPS induced by AP medication were assessed using the Simpson– Given a set of gene products, the sub-network defined by them can easily Angus Scale, and were followed up for four weeks. Eight participants be determined by mapping all members onto the interactome. The presented EPS, including acute dystonia (N = 5), and drug-induced minimum connected network (MCN), defined as the shortest network that parkinsonism (muscle rigidity and bradykinesia) (N = 3). Two participants connects all the interacting nodes within a gene list, can be deduced
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