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1
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Scarpa JR, Elemento O. Multi-omic molecular profiling and network biology for precision anaesthesiology: a narrative review. Br J Anaesth 2023:S0007-0912(23)00125-3. [PMID: 37055274 DOI: 10.1016/j.bja.2023.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/21/2023] [Accepted: 03/04/2023] [Indexed: 04/15/2023] Open
Abstract
Technological advancement, data democratisation, and decreasing costs have led to a revolution in molecular biology in which the entire set of DNA, RNA, proteins, and various other molecules - the 'multi-omic' profile - can be measured in humans. Sequencing 1 million bases of human DNA now costs US$0.01, and emerging technologies soon promise to reduce the cost of sequencing the whole genome to US$100. These trends have made it feasible to sample the multi-omic profile of millions of people, much of which is publicly available for medical research. Can anaesthesiologists use these data to improve patient care? This narrative review brings together a rapidly growing literature in multi-omic profiling across numerous fields that points to the future of precision anaesthesiology. Here, we discuss how DNA, RNA, proteins, and other molecules interact in molecular networks that can be used for preoperative risk stratification, intraoperative optimisation, and postoperative monitoring. This literature provides evidence for four fundamental insights: (1) Clinically similar patients have different molecular profiles and, as a consequence, different outcomes. (2) Vast, publicly available, and rapidly growing molecular datasets have been generated in chronic disease patients and can be repurposed to estimate perioperative risk. (3) Multi-omic networks are altered in the perioperative period and influence postoperative outcomes. (4) Multi-omic networks can serve as empirical, molecular measurements of a successful postoperative course. With this burgeoning universe of molecular data, the anaesthesiologist-of-the-future will tailor their clinical management to an individual's multi-omic profile to optimise postoperative outcomes and long-term health.
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Affiliation(s)
- Joseph R Scarpa
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
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2
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Levings D, Shaw KE, Lacher SE. Genomic resources for dissecting the role of non-protein coding variation in gene-environment interactions. Toxicology 2020; 441:152505. [PMID: 32450112 DOI: 10.1016/j.tox.2020.152505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 12/27/2022]
Abstract
The majority of single nucleotide variants (SNVs) identified in Genome Wide Association Studies (GWAS) fall within non-protein coding DNA and have the potential to alter gene expression. Non-protein coding DNA can control gene expression by acting as transcription factor (TF) binding sites or by regulating the organization of DNA into chromatin. SNVs in non-coding DNA sequences can disrupt TF binding and chromatin structure and this can result in pathology. Further, environmental health studies have shown that exposure to xenobiotics can disrupt the ability of TFs to regulate entire gene networks and result in pathology. However, there is a large amount of interindividual variability in exposure-linked health outcomes. One explanation for this heterogeneity is that genetic variation and exposure combine to disrupt gene regulation, and this eventually manifests in disease. Many resources exist that annotate common variants from GWAS and combine them with conservation, functional genomics, and TF binding data. These annotation tools provide clues regarding the biological implications of an SNV, as well as lead to the generation of hypotheses regarding potentially disrupted target genes, epigenetic markers, pathways, and cell types. Collectively this information can be used to predict how SNVs can alter an individual's response to exposure and disease risk. A basic understanding of the regulatory information contained within non-protein coding DNA is needed to predict the biological consequences of SNVs, and to determine how these SNVs impact exposure-related disease. We hope that this review will aid in the characterization of disease-associated genetic variation in the non-protein coding genome.
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Affiliation(s)
- Daniel Levings
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, 1035 University Drive, Duluth, MN, 55812, USA
| | - Kirsten E Shaw
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, 1035 University Drive, Duluth, MN, 55812, USA
| | - Sarah E Lacher
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, 1035 University Drive, Duluth, MN, 55812, USA.
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3
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Scott SA, Owusu Obeng A, Botton MR, Yang Y, Scott ER, Ellis SB, Wallsten R, Kaszemacher T, Zhou X, Chen R, Nicoletti P, Naik H, Kenny EE, Vega A, Waite E, Diaz GA, Dudley J, Halperin JL, Edelmann L, Kasarskis A, Hulot JS, Peter I, Bottinger EP, Hirschhorn K, Sklar P, Cho JH, Desnick RJ, Schadt EE. Institutional profile: translational pharmacogenomics at the Icahn School of Medicine at Mount Sinai. Pharmacogenomics 2017; 18:1381-1386. [PMID: 28982267 DOI: 10.2217/pgs-2017-0137] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
For almost 50 years, the Icahn School of Medicine at Mount Sinai has continually invested in genetics and genomics, facilitating a healthy ecosystem that provides widespread support for the ongoing programs in translational pharmacogenomics. These programs can be broadly cataloged into discovery, education, clinical implementation and testing, which are collaboratively accomplished by multiple departments, institutes, laboratories, companies and colleagues. Focus areas have included drug response association studies and allele discovery, multiethnic pharmacogenomics, personalized genotyping and survey-based education programs, pre-emptive clinical testing implementation and novel assay development. This overview summarizes the current state of translational pharmacogenomics at Mount Sinai, including a future outlook on the forthcoming expansions in overall support, research and clinical programs, genomic technology infrastructure and the participating faculty.
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Affiliation(s)
- Stuart A Scott
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.,The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Aniwaa Owusu Obeng
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Department of Pharmacy, the Mount Sinai Medical Center, NY 10029, USA
| | - Mariana R Botton
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Yao Yang
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Erick R Scott
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Stephen B Ellis
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | | | - Tom Kaszemacher
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Xiang Zhou
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Rong Chen
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Paola Nicoletti
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Hetanshi Naik
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Eimear E Kenny
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Aida Vega
- Mount Sinai Faculty Practice Associates Primary Care Program, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Eva Waite
- Mount Sinai Faculty Practice Associates Primary Care Program, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - George A Diaz
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Joel Dudley
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Jonathan L Halperin
- The Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Lisa Edelmann
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Andrew Kasarskis
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Jean-Sébastien Hulot
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, UMRS_1166 ICAN, Institute of Cardiometabolism & Nutrition, AP-HP, Pitié-Salpêtrière Hospital, Institute of Cardiology, Paris, France
| | - Inga Peter
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Erwin P Bottinger
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Berlin Institute of Health, Berlin, Germany
| | - Kurt Hirschhorn
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Pamela Sklar
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Department of Psychiatry & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Judy H Cho
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, NY 10029 USA
| | - Robert J Desnick
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Eric E Schadt
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY 10029, USA.,Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA
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4
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Meng Q, Zhuang Y, Ying Z, Agrawal R, Yang X, Gomez-Pinilla F. Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders. EBioMedicine 2017; 16:184-194. [PMID: 28174132 PMCID: PMC5474519 DOI: 10.1016/j.ebiom.2017.01.046] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 01/31/2017] [Accepted: 01/31/2017] [Indexed: 12/28/2022] Open
Abstract
The complexity of the traumatic brain injury (TBI) pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing), and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.
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Affiliation(s)
- Qingying Meng
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yumei Zhuang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zhe Ying
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Rahul Agrawal
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| | - Fernando Gomez-Pinilla
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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5
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Boland MR, Jacunski A, Lorberbaum T, Romano JD, Moskovitch R, Tatonetti NP. Systems biology approaches for identifying adverse drug reactions and elucidating their underlying biological mechanisms. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2015; 8:104-22. [PMID: 26559926 DOI: 10.1002/wsbm.1323] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 09/30/2015] [Accepted: 10/01/2015] [Indexed: 01/06/2023]
Abstract
Small molecules are indispensable to modern medical therapy. However, their use may lead to unintended, negative medical outcomes commonly referred to as adverse drug reactions (ADRs). These effects vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. Current methods rely on clinical trials and postmarket surveillance programs to find novel ADRs; however, clinical trials are limited by small sample size, whereas postmarket surveillance methods may be biased and inherently leave patients at risk until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods. In particular, network analysis allows researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large-scale observational health data to predict ADRs in both individual patients and global populations. In this review, we explore the rapid expansion of systems pharmacology in the study of ADRs. We enumerate the existing methods and strategies and illustrate progress in the field with a model framework that incorporates crucial data elements, such as diet and comorbidities, known to modulate ADR risk. Using this framework, we highlight avenues of research that may currently be underexplored, representing opportunities for future work.
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Affiliation(s)
- Mary Regina Boland
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Department of Systems Biology, Columbia University, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA.,Observational Health Data Science and Informatics (OHDSI), New York, NY, USA
| | - Alexandra Jacunski
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Department of Systems Biology, Columbia University, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA.,Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University, New York, NY, USA
| | - Tal Lorberbaum
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Department of Systems Biology, Columbia University, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA.,Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA
| | - Joseph D Romano
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Department of Systems Biology, Columbia University, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA
| | - Robert Moskovitch
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Department of Systems Biology, Columbia University, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA
| | - Nicholas P Tatonetti
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Department of Systems Biology, Columbia University, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA.,Observational Health Data Science and Informatics (OHDSI), New York, NY, USA
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6
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Mas S, Gassó P, Lafuente A. Applicability of gene expression and systems biology to develop pharmacogenetic predictors; antipsychotic-induced extrapyramidal symptoms as an example. Pharmacogenomics 2015; 16:1975-88. [PMID: 26556470 DOI: 10.2217/pgs.15.134] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Pharmacogenetics has been driven by a candidate gene approach. The disadvantage of this approach is that is limited by our current understanding of the mechanisms by which drugs act. Gene expression could help to elucidate the molecular signatures of antipsychotic treatments searching for dysregulated molecular pathways and the relationships between gene products, especially protein-protein interactions. To embrace the complexity of drug response, machine learning methods could help to identify gene-gene interactions and develop pharmacogenetic predictors of drug response. The present review summarizes the applicability of the topics presented here (gene expression, network analysis and gene-gene interactions) in pharmacogenetics. In order to achieve this, we present an example of identifying genetic predictors of extrapyramidal symptoms induced by antipsychotic.
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Affiliation(s)
- Sergi Mas
- Department of Pathological Anatomy, Pharmacology & Microbiology, University of Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain
| | - Patricia Gassó
- Department of Pathological Anatomy, Pharmacology & Microbiology, University of Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Amelia Lafuente
- Department of Pathological Anatomy, Pharmacology & Microbiology, University of Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain
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7
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Kelder T, Verschuren L, van Ommen B, van Gool AJ, Radonjic M. Network signatures link hepatic effects of anti-diabetic interventions with systemic disease parameters. BMC SYSTEMS BIOLOGY 2014; 8:108. [PMID: 25204982 PMCID: PMC4363943 DOI: 10.1186/s12918-014-0108-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 08/29/2014] [Indexed: 11/10/2022]
Abstract
Background Multifactorial diseases such as type 2 diabetes mellitus (T2DM), are driven by a complex network of interconnected mechanisms that translate to a diverse range of complications at the physiological level. To optimally treat T2DM, pharmacological interventions should, ideally, target key nodes in this network that act as determinants of disease progression. Results We set out to discover key nodes in molecular networks based on the hepatic transcriptome dataset from a preclinical study in obese LDLR-/- mice recently published by Radonjic et al. Here, we focus on comparing efficacy of anti-diabetic dietary (DLI) and two drug treatments, namely PPARA agonist fenofibrate and LXR agonist T0901317. By combining knowledge-based and data-driven networks with a random walks based algorithm, we extracted network signatures that link the DLI and two drug interventions to dyslipidemia-related disease parameters. Conclusions This study identified specific and prioritized sets of key nodes in hepatic molecular networks underlying T2DM, uncovering pathways that are to be modulated by targeted T2DM drug interventions in order to modulate the complex disease phenotype.
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Affiliation(s)
- Thomas Kelder
- TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. .,Current address: EdgeLeap B.V, Utrecht, The Netherlands.
| | - Lars Verschuren
- TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands.
| | - Ben van Ommen
- TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands.
| | - Alain J van Gool
- TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. .,Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. .,Faculty of Physics, Mathematics and Informatics, Radboud University Nijmegen, Nijmegen, The Netherlands.
| | - Marijana Radonjic
- TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. .,Current address: EdgeLeap B.V, Utrecht, The Netherlands.
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8
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Das SK, Sharma NK. Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility. World J Diabetes 2014; 5:97-114. [PMID: 24748924 PMCID: PMC3990322 DOI: 10.4239/wjd.v5.i2.97] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 02/21/2014] [Accepted: 03/14/2014] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes (T2D) is a common metabolic disorder which is caused by multiple genetic perturbations affecting different biological pathways. Identifying genetic factors modulating the susceptibility of this complex heterogeneous metabolic phenotype in different ethnic and racial groups remains challenging. Despite recent success, the functional role of the T2D susceptibility variants implicated by genome-wide association studies (GWAS) remains largely unknown. Genetic dissection of transcript abundance or expression quantitative trait (eQTL) analysis unravels the genomic architecture of regulatory variants. Availability of eQTL information from tissues relevant for glucose homeostasis in humans opens a new avenue to prioritize GWAS-implicated variants that may be involved in triggering a causal chain of events leading to T2D. In this article, we review the progress made in the field of eQTL research and knowledge gained from those studies in understanding transcription regulatory mechanisms in human subjects. We highlight several novel approaches that can integrate eQTL analysis with multiple layers of biological information to identify ethnic-specific causal variants and gene-environment interactions relevant to T2D pathogenesis. Finally, we discuss how the eQTL analysis mediated search for “missing heritability” may lead us to novel biological and molecular mechanisms involved in susceptibility to T2D.
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9
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Yoshikawa T, Kanazawa H, Fujimoto S, Hirata K. Epistatic effects of multiple receptor genes on pathophysiology of asthma - its limits and potential for clinical application. Med Sci Monit 2014; 20:64-71. [PMID: 24435185 PMCID: PMC3907491 DOI: 10.12659/msm.889754] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 11/09/2013] [Indexed: 01/31/2023] Open
Abstract
To date, genome-wide association studies (GWAS) permit a comprehensive scan of the genome in an unbiased manner, with high sensitivity, and thereby have the potential to identify candidate genes for the prevalence or development of multifactorial diseases such as bronchial asthma. However, most studies have only managed to explain a small additional percentage of hereditability estimates, and often fail to show consistent results among studies despite large sample sizes. Epistasis is defined as the interaction between multiple different genes affecting phenotypes. By applying epistatic analysis to clinical genetic research, we can analyze interactions among more than 2 molecules (genes) considering the whole system of the human body, illuminating dynamic molecular mechanisms. An increasing number of genetic studies have investigated epistatic effects on the risk for development of asthma. The present review highlights a concept of epistasis to overcome traditional genetic studies in humans and provides an update of evidence on epistatic effects on asthma. Furthermore, we review concerns regarding recent trends in epistatic analyses from the perspective of clinical physicians. These concerns include biological plausibility of genes identified by computational statistics, and definition of the diagnostic label of 'physician-diagnosed asthma'. In terms of these issues, further application of epistatic analysis will prompt identification of susceptibility of diseases and lead to the development of a new generation of pharmacological strategies to treat asthma.
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Affiliation(s)
- Takahiro Yoshikawa
- Department of Sports Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroshi Kanazawa
- Department of Respiratory Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shigeo Fujimoto
- Department of Sports Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kazuto Hirata
- Department of Respiratory Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
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10
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Tang J, Aittokallio T. Network pharmacology strategies toward multi-target anticancer therapies: from computational models to experimental design principles. Curr Pharm Des 2014; 20:23-36. [PMID: 23530504 PMCID: PMC3894695 DOI: 10.2174/13816128113199990470] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 03/18/2013] [Indexed: 12/12/2022]
Abstract
Polypharmacology has emerged as novel means in drug discovery for improving treatment response in clinical use. However, to really capitalize on the polypharmacological effects of drugs, there is a critical need to better model and understand how the complex interactions between drugs and their cellular targets contribute to drug efficacy and possible side effects. Network graphs provide a convenient modeling framework for dealing with the fact that most drugs act on cellular systems through targeting multiple proteins both through on-target and off-target binding. Network pharmacology models aim at addressing questions such as how and where in the disease network should one target to inhibit disease phenotypes, such as cancer growth, ideally leading to therapies that are less vulnerable to drug resistance and side effects by means of attacking the disease network at the systems level through synergistic and synthetic lethal interactions. Since the exponentially increasing number of potential drug target combinations makes pure experimental approach quickly unfeasible, this review depicts a number of computational models and algorithms that can effectively reduce the search space for determining the most promising combinations for experimental evaluation. Such computational-experimental strategies are geared toward realizing the full potential of multi-target treatments in different disease phenotypes. Our specific focus is on system-level network approaches to polypharmacology designs in anticancer drug discovery, where we give representative examples of how network-centric modeling may offer systematic strategies toward better understanding and even predicting the phenotypic responses to multi-target therapies.
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11
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12
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Konry T, Lerner A, Yarmush ML, Smolina IV. Target DNA detection and quantitation on a single cell with single base resolution. TECHNOLOGY 2013; 1:88. [PMID: 24977169 PMCID: PMC4073798 DOI: 10.1142/s2339547813500088] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
In this report, we present a new method for sensitive detection of short DNA sites in single cells with single base resolution. The method combines peptide nucleic acid (PNA) openers as the tagging probes, together with isothermal rolling circle amplification (RCA) and fluorescence-based detection, all performed in a cells-in-flow format. Bis-PNAs provide single base resolution, while RCA ensures linear signal amplification. We applied this method to detect the oncoviral DNA inserts in cancer cell lines using a flow-cytometry system. We also demonstrated quantitative detection of the selected signature sites within single cells in microfluidic nano-liter droplets. Our results show single-nucleotide polymorphism (SNP) discrimination and detection of copy-number variations (CNV) under isothermal non-denaturing conditions. This new method is ideal for many applications in which ultra-sensitive DNA characterization with single base resolution is desired on the level of single cells.
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Ma H, Zhao H. Drug target inference through pathway analysis of genomics data. Adv Drug Deliv Rev 2013; 65:966-72. [PMID: 23369829 DOI: 10.1016/j.addr.2012.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/21/2012] [Accepted: 12/22/2012] [Indexed: 10/27/2022]
Abstract
Statistical modeling coupled with bioinformatics is commonly used for drug discovery. Although there exist many approaches for single target based drug design and target inference, recent years have seen a paradigm shift to system-level pharmacological research. Pathway analysis of genomics data represents one promising direction for computational inference of drug targets. This article aims at providing a comprehensive review on the evolving issues in this field, covering methodological developments, their pros and cons, as well as future research directions.
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Valsesia A, Macé A, Jacquemont S, Beckmann JS, Kutalik Z. The Growing Importance of CNVs: New Insights for Detection and Clinical Interpretation. Front Genet 2013; 4:92. [PMID: 23750167 PMCID: PMC3667386 DOI: 10.3389/fgene.2013.00092] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 05/04/2013] [Indexed: 02/03/2023] Open
Abstract
Differences between genomes can be due to single nucleotide variants, translocations, inversions, and copy number variants (CNVs, gain or loss of DNA). The latter can range from sub-microscopic events to complete chromosomal aneuploidies. Small CNVs are often benign but those larger than 500 kb are strongly associated with morbid consequences such as developmental disorders and cancer. Detecting CNVs within and between populations is essential to better understand the plasticity of our genome and to elucidate its possible contribution to disease. Hence there is a need for better-tailored and more robust tools for the detection and genome-wide analyses of CNVs. While a link between a given CNV and a disease may have often been established, the relative CNV contribution to disease progression and impact on drug response is not necessarily understood. In this review we discuss the progress, challenges, and limitations that occur at different stages of CNV analysis from the detection (using DNA microarrays and next-generation sequencing) and identification of recurrent CNVs to the association with phenotypes. We emphasize the importance of germline CNVs and propose strategies to aid clinicians to better interpret structural variations and assess their clinical implications.
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Affiliation(s)
- Armand Valsesia
- Genetics Core, Nestlé Institute of Health Sciences Lausanne, Switzerland
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15
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Pandey G, Zhang B, Jian L. Predicting submicron air pollution indicators: a machine learning approach. ENVIRONMENTAL SCIENCE. PROCESSES & IMPACTS 2013; 15:996-1005. [PMID: 23535697 DOI: 10.1039/c3em30890a] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
The regulation of air pollutant levels is rapidly becoming one of the most important tasks for the governments of developing countries, especially China. Submicron particles, such as ultrafine particles (UFP, aerodynamic diameter ≤ 100 nm) and particulate matter ≤ 1.0 micrometers (PM1.0), are an unregulated emerging health threat to humans, but the relationships between the concentration of these particles and meteorological and traffic factors are poorly understood. To shed some light on these connections, we employed a range of machine learning techniques to predict UFP and PM1.0 levels based on a dataset consisting of observations of weather and traffic variables recorded at a busy roadside in Hangzhou, China. Based upon the thorough examination of over twenty five classifiers used for this task, we find that it is possible to predict PM1.0 and UFP levels reasonably accurately and that tree-based classification models (Alternating Decision Tree and Random Forests) perform the best for both these particles. In addition, weather variables show a stronger relationship with PM1.0 and UFP levels, and thus cannot be ignored for predicting submicron particle levels. Overall, this study has demonstrated the potential application value of systematically collecting and analysing datasets using machine learning techniques for the prediction of submicron sized ambient air pollutants.
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Affiliation(s)
- Gaurav Pandey
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, NY 10029, USA
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Meng Q, Mäkinen VP, Luk H, Yang X. Systems Biology Approaches and Applications in Obesity, Diabetes, and Cardiovascular Diseases. CURRENT CARDIOVASCULAR RISK REPORTS 2013; 7:73-83. [PMID: 23326608 PMCID: PMC3543610 DOI: 10.1007/s12170-012-0280-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The metabolically connected triad of obesity, diabetes, and cardiovascular diseases is a major public health threat, and is expected to worsen due to the global shift toward energy-rich and sedentary living. Despite decades of intense research, a large part of the molecular pathogenesis behind complex metabolic diseases remains unknown. Recent advances in genetics, epigenomics, transcriptomics, proteomics and metabolomics enable us to obtain large-scale snapshots of the etiological processes in multiple disease-related cells, tissues and organs. These datasets provide us with an opportunity to go beyond conventional reductionist approaches and to pinpoint the specific perturbations in critical biological processes. In this review, we summarize systems biology methodologies such as functional genomics, causality inference, data-driven biological network construction, and higher-level integrative analyses that can produce novel mechanistic insights, identify disease biomarkers, and uncover potential therapeutic targets from a combination of omics datasets. Importantly, we also demonstrate the power of these approaches by application examples in obesity, diabetes, and cardiovascular diseases.
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Affiliation(s)
- Qingying Meng
- Department of Integrative Biology and Physiology, University of California (UCLA), 610 Charles E. Young Dr E., Terasaki Life Sciences Building, Los Angeles, CA 90095 USA
| | - Ville-Petteri Mäkinen
- Department of Integrative Biology and Physiology, University of California (UCLA), 610 Charles E. Young Dr E., Terasaki Life Sciences Building, Los Angeles, CA 90095 USA
| | - Helen Luk
- Department of Integrative Biology and Physiology, University of California (UCLA), 610 Charles E. Young Dr E., Terasaki Life Sciences Building, Los Angeles, CA 90095 USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California (UCLA), 610 Charles E. Young Dr E., Terasaki Life Sciences Building, Los Angeles, CA 90095 USA
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Pathway analysis reveals common pro-survival mechanisms of metyrapone and carbenoxolone after traumatic brain injury. PLoS One 2013; 8:e53230. [PMID: 23326402 PMCID: PMC3541279 DOI: 10.1371/journal.pone.0053230] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2012] [Accepted: 11/26/2012] [Indexed: 11/19/2022] Open
Abstract
Developing new pharmacotherapies for traumatic brain injury (TBI) requires elucidation of the neuroprotective mechanisms of many structurally and functionally diverse compounds. To test our hypothesis that diverse neuroprotective drugs similarly affect common gene targets after TBI, we compared the effects of two drugs, metyrapone (MT) and carbenoxolone (CB), which, though used clinically for noncognitive conditions, improved learning and memory in rats and humans. Although structurally different, both MT and CB inhibit a common molecular target, 11β hydroxysteroid dehydrogenase type 1, which converts inactive cortisone to cortisol, thereby effectively reducing glucocorticoid levels. We examined injury-induced signaling pathways to determine how the effects of these two compounds correlate with pro-survival effects in surviving neurons of the injured rat hippocampus. We found that treatment of TBI rats with MT or CB acutely induced in hippocampal neurons transcriptional profiles that were remarkably similar (i.e., a coordinated attenuation of gene expression across multiple injury-induced cell signaling networks). We also found, to a lesser extent, a coordinated increase in cell survival signals. Analysis of injury-induced gene expression altered by MT and CB provided additional insight into the protective effects of each. Both drugs attenuated expression of genes in the apoptosis, death receptor and stress signaling pathways, as well as multiple genes in the oxidative phosphorylation pathway such as subunits of NADH dehydrogenase (Complex1), cytochrome c oxidase (Complex IV) and ATP synthase (Complex V). This suggests an overall inhibition of mitochondrial function. Complex 1 is the primary source of reactive oxygen species in the mitochondrial oxidative phosphorylation pathway, thus linking the protective effects of these drugs to a reduction in oxidative stress. The net effect of the drug-induced transcriptional changes observed here indicates that suppressing expression of potentially harmful genes, and also, surprisingly, reduced expression of pro-survival genes may be a hallmark of neuroprotective therapeutic effects.
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18
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Decoding dendritic cell function through module and network analysis. J Immunol Methods 2013; 387:71-80. [DOI: 10.1016/j.jim.2012.09.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 09/17/2012] [Indexed: 01/08/2023]
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Feng Q, Wilke RA, Baye TM. Individualized risk for statin-induced myopathy: current knowledge, emerging challenges and potential solutions. Pharmacogenomics 2012; 13:579-94. [PMID: 22462750 DOI: 10.2217/pgs.12.11] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Skeletal muscle toxicity is the primary adverse effect of statins. In this review, we summarize current knowledge regarding the genetic and nongenetic determinants of risk for statin induced myopathy. Many genetic factors were initially identified through candidate gene association studies limited to pharmacokinetic (PK) targets. Through genome-wide association studies, it has become clear that SLCO1B1 is among the strongest PK predictors of myopathy risk. Genome-wide association studies have also expanded our understanding of pharmacodynamic candidate genes, including RYR2. It is anticipated that deep resequencing efforts will define new loci with rare variants that also contribute, and sophisticated computational approaches will be needed to characterize gene-gene and gene-environment interactions. Beyond environment, race is a critical covariate, and its influence is only partly explained by geographic differences in the frequency of known pharmacodynamic and PK variants. As such, admixture analyses will be essential for a full understanding of statin-induced myopathy.
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Affiliation(s)
- QiPing Feng
- Department of Medicine, Vanderbilt University Medical Center, Oates Institute for Experimental Therapeutics, Nashville, TN, USA
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Schwartz SM, Schwartz HT, Horvath S, Schadt E, Lee SI. A systematic approach to multifactorial cardiovascular disease: causal analysis. Arterioscler Thromb Vasc Biol 2012; 32:2821-35. [PMID: 23087359 DOI: 10.1161/atvbaha.112.300123] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The combination of systems biology and large data sets offers new approaches to the study of cardiovascular diseases. These new approaches are especially important for the common cardiovascular diseases that have long been described as multifactorial. This promise is undermined by biologists' skepticism of the spider web-like network diagrams required to analyze these large data sets. Although these spider webs resemble composites of the familiar biochemical pathway diagrams, the complexity of the webs is overwhelming. As a result, biologists collaborate with data analysts whose mathematical methods seem much like those of experts using Ouija boards. To make matters worse, it is not evident how to design experiments when the network implies that many molecules must be part of the disease process. Our goal is to remove some of this mystery and suggest a simple experimental approach to the design of experiments appropriate for such analysis. We will attempt to explain how combinations of data sets that include all possible variables, graphical diagrams, complementation of different data sets, and Bayesian analyses now make it possible to determine the causes of multifactorial cardiovascular disease. We will describe this approach using the term causal analysis. Finally, we will describe how causal analysis is already being used to decipher the interactions among cytokines as causes of cardiovascular disease.
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Abstract
Early genome-wide association studies (GWAS) using relatively small samples have identified both rare and common genetic variants with large impact on severe adverse drug reactions, dosing, and efficacy. Here we outline the challenges and recent successes of the GWAS approach in disease genetics and the ways in which these can be applied to pharmacogenomics for biological discovery, determination of heritability, and personalized treatment. We highlight that the genetic architecture of drug efficacy reflects a complex trait yet that of adverse drug reactions more closely mirrors the architecture of Mendelian diseases and how this difference affects future study design. Given that multiple layers of biological data are increasingly available on large samples from biorepositories linked to electronic medical records, GWAS will remain a key component of the systems biology approach to uncovering small to moderate genetic determinants of drug response; these discoveries should move us closer to a personalized approach to health care.
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Affiliation(s)
- Kaixin Zhou
- Medical Research Institute, University of Dundee, Scotland, United Kingdom DD1 9SY.
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Improved insulin sensitivity after treatment with PPARγ and PPARα ligands is mediated by genetically modulated transcripts. Pharmacogenet Genomics 2012; 22:484-97. [PMID: 22437669 DOI: 10.1097/fpc.0b013e328352a72e] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES We aimed to define the effects of peroxisomal proliferator-activated receptor γ (PPARγ) and PPARα agonist mono and combination therapy on adipose tissue and skeletal muscle gene expression in relation to insulin sensitivity. We further investigated the role of genetic polymorphisms in PPAR ligand-modulated genes in transcriptional regulation and glucose homeostasis. MATERIALS AND METHODS Genome-wide transcript profiles of subcutaneous adipose and skeletal muscle and metabolic phenotypes were assessed before and after 10 weeks of pioglitazone and fenofibrate mono or combination therapy in 26 patients with impaired glucose tolerance. To establish the functional role of single nucleotide polymorphisms (SNPs) in genes modulated by pioglitazone alone or in combination with fenofibrate, we examined genome-wide association data of continuous glycemic phenotypes from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium study and adipose eQTL data from the Multi Tissue Human Expression Resource study. RESULTS PPARγ, alone or in combination with PPARα agonists, mediated upregulation of genes involved in the TCA cycle, branched-chain amino acid (BCAA) metabolism, fatty acid metabolism, PPAR signaling, AMPK and cAMP signaling, and insulin signaling pathways, and downregulation of genes in antigen processing and presentation, and immune and inflammatory response in adipose tissue. Remarkably few changes were found in muscle. Strong enrichment of genes involved in propanoate metabolism, fatty acid elongation in the mitochondria, and acetyl-CoA metabolic process were observed only in adipose tissue of the combined pioglitazone and fenofibrate treatment group. After examining Meta-Analyses of Glucose and Insulin-Related Traits Consortium data, SNPs in 22 genes modulated by PPAR ligands were associated with fasting plasma glucose and the expression of 28 transcripts modulated by PPAR ligands was under control of local genetic regulators (cis-eQTLs) in adipose tissue of Multi Tissue Human Expression Resource study twins. CONCLUSION We found differences in transcriptional mechanisms that may describe the insulin-sensitizing effects of PPARγ agonist monotherapy or in combination with a PPARα agonist. The regulatory and glucose homeostasis trait-associated SNPs in PPAR agonist-modulated genes are important candidates for future studies that may explain the interindividual variability in response to thiazolidinedione and fenofibrate treatment.
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Iorio F, Rittman T, Ge H, Menden M, Saez-Rodriguez J. Transcriptional data: a new gateway to drug repositioning? Drug Discov Today 2012; 18:350-7. [PMID: 22897878 PMCID: PMC3625109 DOI: 10.1016/j.drudis.2012.07.014] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 07/19/2012] [Accepted: 07/26/2012] [Indexed: 11/26/2022]
Abstract
Recent advances in computational biology suggest that any perturbation to the transcriptional programme of the cell can be summarised by a proper ‘signature’: a set of genes combined with a pattern of expression. Therefore, it should be possible to generate proxies of clinicopathological phenotypes and drug effects through signatures acquired via DNA microarray technology. Gene expression signatures have recently been assembled and compared through genome-wide metrics, unveiling unexpected drug–disease and drug–drug ‘connections’ by matching corresponding signatures. Consequently, novel applications for existing drugs have been predicted and experimentally validated. Here, we describe related methods, case studies and resources while discussing challenges and benefits of exploiting existing repositories of microarray data that could serve as a search space for systematic drug repositioning.
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Affiliation(s)
- Francesco Iorio
- EMBL – European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK
- Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK
| | - Timothy Rittman
- Dept of Clinical Neurosciences, Herchel Smith Building, Forvie Site, Addenbrooke's Hospital, Robinson Way, Cambridge CB2 0SZ, UK
| | - Hong Ge
- Dept of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, Wilberforce Road, Cambridge CB3 0WA, UK
| | - Michael Menden
- EMBL – European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK
| | - Julio Saez-Rodriguez
- EMBL – European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK
- Corresponding author:.
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Ku CS, Cooper DN, Roukos DH. The ‘sequence everything’ approach and personalized clinical decision challenges. Expert Rev Mol Diagn 2012; 12:319-22. [DOI: 10.1586/erm.12.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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