Handbook of Pharmacogenomics and Stratified Medicine This page is intentionally left blank Handbook of Pharmacogenomics and Stratified Medicine Sandosh Padmanabhan Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD • PARIS SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Copyright Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA © 2014 Elsevier Inc. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher. 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British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-386882-4 For information on all Academic Press publications visit our website at store.elsevier.com Typeset by SPS www.sps.co.in Printed and bound in the United States of America 14 15 16 17 18 10 9 8 7 6 5 4 3 2 1 Dedication For Sumana and Shashank v This page is intentionally left blank Contents Contributors xv 3. The Human Genome, Gene Foreword xix Regulation, and Genomic Variation 41 Preface xxi Acknowledgements xxiii Kathleen M. Murphy, Aislinn Cooper, and Edward S. Tobias Part I 3.1 Overview: Structure of the Human Genome 41 3.2 Gene Structures 44 Introduction 3.3 Gene Expression 45 3.4 Gene Regulation 46 1. Pharmacogenomics and Stratified 3.5 Genomic Variation 51 Medicine 3 3.6 Conclusion 56 References 56 Sandosh Padmanabhan 1.1 Overview 3 4. Epigenetics 57 1.2 The Genetic Basis of Drug Response and Adverse Effects 5 Tony McBryan and Peter D. Adams 1.3 Single-Gene Studies 5 4.1 Overview 57 1.4 Genome-Wide Association Studies in Pharmacogenomics 12 4.2 DNA Methylation 57 1.5 The Road to Personalization and Stratification 13 4.3 Histones and Variants 61 1.6 Pharmacogenetic Biomarkers and 4.4 Epigenetic Disorders and Therapies 65 Companion Diagnostics 13 4.5 Conclusion 66 1.7 Economic Challenges 19 References 66 1.8 Conclusions 21 References 22 Part III Part II Experimental and Discovery Platforms Basic Genetics 5. Animal Models in 2. Basic Genetics: The Cell, Mitosis Pharmacogenomics 73 and Meiosis, and Mendelian Laws 29 Erin Olson and Delyth Graham Guan Wang 5.1 Overview 73 2.1 Overview of the Cell: Anatomy, Components, and Function 29 5.2 Rodent Models 74 2.2 Cell Reproduction: Cell Cycle and Mitosis 30 5.3 Nonrodent Models of Human Disease 79 2.3 Meiosis 33 5.4 Genetic/Genomic Resources 79 2.4 Mendelian Laws 35 5.5 Ethical Issues of Animal Experimentation 80 2.5 Public Databases for Biomedical Research 5.6 Caution and Limitations 80 in Humans 38 5.7 Applications of in vivo Models in 2.6 Conclusion 39 Pharmacogenomic Research 81 Glossary 39 5.8 Rodent Models in Pharmacogenomics 82 Acknowledgments 40 5.9 Conclusion 85 References 40 References 85 vii viii Contents 6. Human Lymphoblastoid Cell Lines in 10. Metabolomics 181 Pharmacogenomics 89 Karl Burgess, Naomi Rankin, and Stefan Weidt Jae-Pil Jeon 10.1 Overview 181 6.1 Overview 89 10.2 Metabolomics Techniques 6.2 Generation of LCLs 90 and Technologies 184 6.3 Biological Characteristics of LCLs 95 10.3 Analytical Platform 187 6.4 Potentials and Limitations of LCL 10.4 Analysis of Metabolomic Data 197 Applications 97 10.5 Conclusion 200 6.5 Future Perspectives 105 References 201 Acknowledgments 107 References 107 11. Stem Cells 207 7. Liver Expression Quantitative Trait Komal Loya Loci (eQTL) and Related Approaches 11.1 Overview 207 in Pharmacogenomic Studies 111 11.2 Stem Cell Types 208 11.3 Stem Cell Culture Methods 211 Dylan M. Glubb, Amy S. Etheridge, Eric Seiser, 11.4 Molecular Signatures of Stem Cells 212 and Federico Innocenti 11.5 Epigenomics of Stem Cells 215 7.1 Overview 111 11.6 Pharmacogenomics of Stem Cells 218 7.2 Liver eQTL Studies 112 11.7 Potential of Stem Cells 219 7.3 Future Directions 117 11.8 Future Prospects 226 7.4 Conclusion 120 Abbreviations 227 Acknowledgments 120 References 228 Glossary 121 Acronyms and Abbreviations 121 Part IV References 121 Statistics, Bioinformatics 8. Next-Generation Sequencing 125 and Databases Pawel Herzyk 12. Fundamentals of Complex Trait 8.1 Overview 125 Genetics and Association Studies 235 8.2 First-Generation Sequencing: Chain Termination Method 125 Jahad Alghamdi and Sandosh Padmanabhan 8.3 The Concept of Next-Generation Sequencing 126 12.1 Overview 235 8.4 Application-Independent Data Analysis 129 12.2 The Phenotype 235 8.5 Genomic Applications 131 12.3 Population Genetics 239 8.6 Transcriptomic Applications 133 12.4 Association Studies 247 8.7 Epigenomic Applications 135 12.5 Conclusions 256 8.8 Metagenomic Applications 137 References 256 8.9 Conclusions 141 References 141 13. Bioinformatics: Concepts, Methods, and Data 259 9. Proteomics 147 Scott W. Robinson, Avid M. Afzal, Holger Husi and Amaya Albalat and David P. Leader 9.1 Overview 147 13.1 Overview 259 9.2 Data Acquisition 148 13.2 A nalysis of Sequences of Nucleic Acids 9.3 Data Analysis 163 and Proteins 260 9.4 Discovery and Validation 167 13.3 Molecular Evolution and Phylogenetics 264 9.5 Personalized Medicine 172 13.4 Molecular Graphics and Protein Modeling 269 9.6 Conclusions 172 13.5 Bioinformatics Databases 276 Acronyms 173 Glossary 284 References 173 References 284 Contents ix 14. PharmGKB: The Pharmacogenomics 17. Pharmacokinetic Knowledgebase 289 Pharmacogenomics 341 Julia M. Barbarino, Michelle Whirl-Carrillo, Safaa Mohammed M. Alsanosi, Craig Teri E. Klein, and Russ B. Altman Skiffington, and Sandosh Padmanabhan 14.1 Overview 289 17.1 Overview 341 14.2 The PharmGKB Website 290 17.2 Principles of Pharmacokinetics 341 14.3 Variant Annotations 291 17.3 ADME: Pharmacogenomics 349 14.4 Clinical Annotations 294 17.4 Conclusions 360 14.5 VIPs and Pathways 297 References 361 14.6 Clinical Implementation: Consortia, CPIC, and Dosing Guidelines 301 18. Pharmacodynamic 14.7 Projects in Development 303 14.8 Conclusion 304 Pharmacogenomics 365 Glossary 305 Acronyms and Abbreviations 305 Linsay McCallum, Stefanie Lip, Acknowledgments 306 and Sandosh Padmanabhan References 306 18.1 Overview 365 18.2 Basic Pharmacodynamics 365 Part V 18.3 Pharmacodynamic Pharmacogenetics 373 Clinical Trials 18.4 Conclusion: Pharmacodynamic Pharmacogenomics into 15. Clinical Trials in Pharmacogenomics Clinical Practice 379 and Stratified Medicine 309 Glossary 380 Acronyms and Abbreviations 381 Sandosh Padmanabhan References 381 15.1 Overview 309 15.2 Phase I Studies 309 19. MicroRNA: Regulation of P450 15.3 Phase II Studies 312 and Pharmacogenetics 385 15.4 Phase III Studies 314 15.5 Phase IV Trials 319 Miki Nakajima and Tsuyoshi Yokoi 15.6 Retrospective Analysis of Clinical Datasets 319 19.1 Overview 385 References 319 19.2 miRNA Biogenesis 385 19.3 miRNA Function 386 19.4 miRNA Target Identification 386 Part VI 19.5 Regulation of Drug-Metabolizing P450s 389 Fundamental Pharmacogenomics 19.6 Regulation of Cancer-Related P450s 391 16. CYP450 and Ethnicity 323 19.7 Modulation of miRNA Expression and its Toxicological Outcome 394 Joseph McGraw 19.8 miRNA Pharmacogenetics Associated with Disease or Drug Response 395 16.1 Overview 323 19.9 miRNAs as Biomarkers and 16.2 Variation: Importance of Therapeutic Targets 397 Race/Ethnicity 326 16.3 Variation: CYP450 Phenotyping 327 19.10 miRNAs and Drug Response 397 16.4 CYP450 Variation in Different Racial/Ethnic 19.11 Conclusions 397 Populations—CYP450 Families 329 Glossary 398 16.5 Future Perspectives 337 Abbreviations 398 References 337 References 398