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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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online by visiting the Elsevier website at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use
Elsevier material.

Notices
No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in
the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses
and drug dosages should be made.

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

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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

Contributorsxv 3. The Human Genome, Gene

Forewordxix Regulation, and Genomic Variation 41
Prefacexxi
Acknowledgementsxxiii Kathleen M. Murphy, Aislinn Cooper,
and Edward S. Tobias
3.1 Overview: Structure of the Human Genome 41
Part I 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
Medicine3 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
1.4 Genome-Wide Association Studies in 4.1 Overview 57
­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
Basic Genetics Platforms

2. Basic Genetics: The Cell, Mitosis 5. Animal Models in

and Meiosis, and Mendelian Laws 29 Pharmacogenomics 73

Guan Wang Erin Olson and Delyth Graham

2.1 Overview of the Cell: Anatomy, Components, 5.1 Overview 73

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
References 121
Part IV
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 Analysis 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
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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
14.7 Projects in Development 303 18. Pharmacodynamic
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
P450s389
Fundamental Pharmacogenomics 19.6 Regulation of Cancer-Related
P450s391
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
16.2 Variation: Importance of 19.9 miRNAs as Biomarkers and
Race/Ethnicity 326 Therapeutic Targets 397
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
x Contents

Part VII 23. Hemostasis and Anticoagulants 479

Application in Therapeutics Matthew R. Wilson and R. Campbell Tait
23.1 Overview 479
20. Adverse Drug Reactions 405 23.2 Hemostasis 479
23.3 Indications for Anticoagulation 482
Lauren Walker, Vincent Yip, and 23.4 Parenteral Anticoagulants 484
Munir Pirmohamed 23.5 Oral Anticoagulants 488
20.1 Overview 405 23.6 Conclusion and Directions for
20.2 Phase I Metabolism 408 Future Research 494
20.3 Phase II Metabolism 410 References 494
20.4 Type B Adverse Drug Reactions 414
20.5 Conclusion 424 24. Pharmacogenomics of Warfarin 497
Abbreviations and Acronyms 425
References 426 Ann K. Daly
24.1 Overview 497
21. HLA and the Pharmacogenomics 24.2 Pharmacology of Warfarin 498
of Drug Hypersensitivity 437 24.3 Nongenetic Factors Affecting Warfarin
Dose Requirement 499
Katie D. White, Silvana Gaudieri, and 24.4 Genes with Major Effects on Warfarin
Elizabeth J. Phillips Dose Requirement 500
24.5 Additional Pharmacogenomic Factors
21.1 Overview 437
Affecting Warfarin Dosage 502
21.2 Introduction 437
24.6 Application of Pharmacogenomics to
21.3 Classification of Drug Hypersensitivity
Warfarin Prescription 503
Syndromes 440
24.7 Conclusion and Future Research Directions 504
21.4 Immunopathogenesis of Drug
References 504
Hypersensitivity Syndromes 442
21.5 HLA and Hypersensitivity
Reactions 444 25. Pharmacogenomics of Clopidogrel 509
21.6 Stratified Approaches to Prevent Drug
Hypersensitivity and their Translation Betti Giusti, Claudia Saracini, Silvia Galora,
into Clinical Medicine 455 and Rossella Marcucci
21.7 The Future Direction of Stratified Medicine
25.1 Overview 509
in Drug-Induced Hypersensitivity 458
25.2 Clopidogrel Response Variation 514
Acronyms 459
25.3 Genetic Dissection of
References 459
Clopidogrel Response 518
25.4 Current Status 527
22. Drug-Induced Liver Injury 467 25.5 Conclusions and Future Directions 535
Abbreviations 536
Thomas J. Urban and Hans Tillmann References 536

22.1 Overview 467 26. Pharmacogenetics of Antidepressant

22.2 Epidemiology and Public Health Drugs 543
Impact 467
22.3 Etiology 468 Chiara Fabbri, Alessandro Minarini, Yoshihiko
22.4 Pharmacogenomics and Stratified ­Matsumoto, and Alessandro Serretti
Medicine in DILI 469
22.5 Difficulties in Identifying Biomarkers 26.1 Overview 543
for DILI 470 26.2 Candidate Gene Studies 544
22.6 DILI-Associated Genetic Variants 471 26.3 Genome-Wide Approaches 553
22.7 Utility of Dili Risk Variants in 26.4 Conclusion 555
the Clinic 472 Key Concepts 556
22.8 Future Directions 473 Glossary 556
22.9 Conclusions 475 Acronyms and Abbreviations 556
References 475 References 557
Contents xi

27. Personalized Medicine of 30.4 The Need for Pharmacogenomics and

Alzheimer’s Disease 563 Stratified Medicine 685
30.5 Genetic Variants Associated with
Ramón Cacabelos, Pablo Cacabelos, and Response to Oral Hypoglycemic Agents 685
Clara Torrellas 30.6 Stratified Oral Antidiabetic Medicine:
Pharmacogenomics Application 709
27.1 Overview 563 30.7 Conclusions: Future Perspectives 710
27.2 Toward a Personalized Medicine for Abbreviations 710
Dementia and Neurodegenerative Disorders 564 References 710
27.3 Genomics of Alzheimer’s Disease 565
27.4 Pathogenic Events 565 31. Genomics and Pharmacogenomics
27.5 Biomarkers and Comorbidity 569 of Lipid-Lowering Therapies 715
27.6 Therapeutic Strategies 571
27.7 Pharmacogenomics 573 Kieran F. Docherty and Sandosh Padmanabhan
27.8 Future Perspective 584
27.9 Conclusion 585 31.1 Overview 715
Appendix A 586 31.2 Lipid Metabolism 716
Appendix B 608 31.3 Lipids and CVD Risk, Epidemiology,
References 611 and Public Health Impact 718
31.4 Genetic Basis of Lipid Disorders and
Lipid Levels 722
28. Asthma 617 31.5 Conclusion and Future
Directions 741
Dominick Shaw, Michael Portelli, References 742
and Ian Sayers
28.1 Overview 617 32. Hypertension Pharmacogenomics 747
28.2 Clinical Aspects 618
28.3 Asthma Pathophysiology 623 Yan Gong, Caitrin W. McDonough, Sandosh
28.4 Current Management of Asthma 629 Padmanabhan, and Julie A Johnson
28.5 Stratified Medicine for Asthma 631
28.6 Drug Development in Asthma and 32.1 Overview 747
Emerging Targets 645 32.2 Epidemiology and Public
Health Impact 747
28.7 Conclusions and Future Directions 647
32.3 Genetic Basis of Hypertension 749
Acknowledgments 647
32.4 Need for Stratified Approaches to
References 647
Treatment with Antihypertensives 754
32.5 Pharmacogenomics of Blood Pressure
29. Rheumatoid Arthritis 653 Response to Antihypertensive Drugs 758
32.6 Pharmacogenomics of Antihypertensive
Jisna R Paul, Deepali Sen, and Treatment—Related Outcomes 764
Prabha Ranganathan 32.7 Future Perspectives 771
References 772
29.1 Overview 653
29.2 Pharmacogenetics of Non­biologic
DMARDs 655 33. QTc and Sudden Cardiac Death 779
29.3 Pharmacogenetics of Biologic
DMARDS 668 Catriona Brown and Sandosh Padmanabhan
29.4 Conclusions and Future Directions 674 33.1 Overview 779
References 674 33.2 Genetic Syndromes 784
33.3 Drug-Induced Variation in QTc 787
30. Pharmacogenomics of Oral 33.4 Public Health Impact 796
Antidiabetic Drugs 683 33.5 QTc in New Drug Discovery and
Drug Safety 797
Vangelis G. Manolopoulos 33.6 Pharmacogenomic Studies 798
and Georgia Ragia 33.7 Future Directions 801
Glossary 802
30.1 Overview 683 Acronyms and Abbreviations 803
30.2 Genetic Basis of Diabetes 683 References 803
30.3 Management of Diabetes 684 Suggested Websites 806
xii Contents

34. Stratified Medicine for 38. Pharmacogenomics of

Pancreatic Cancer 807 Antifungal Agents 879
David K. Chang, Nigel B. Jamieson, H.R. Ashbee and M.H. Gilleece
Sean M. Grimmond, and Andrew V. Biankin
38.1 Overview of Antifungal Therapy 879
34.1 Overview 807 38.2 Public Health Impact of Fungal Diseases 886
34.2 Current Treatment Paradigm 807 38.3 The Need for Pharmacogenomics
34.3 Stratified Therapeutic Approach 808 and Stratified Medicine 886
34.4 Preclinical Models of Pancreatic Cancer 812 38.4 Genetic Variability Associated with
34.5 Central Knowledge Database 812 Antifungal Drugs 887
34.6 Biorepository and Privacy Issues 813 38.5 Current Successes in Stratified
34.7 Conclusion 813 Medicine 895
References 813 38.6 Future Perspectives 896
References 896
35. Pharmacogenomics in Anesthesia 815
Shiv Kumar Singh and Tushar Dixit 39. Advances in Understanding and
Treatment of Human African
35.1 Overview 815
35.2 Pharmacokinetic Pharmacogenetics
Trypanosomiasis: Divergent Diseases
In Anesthesia 815 Caused by Distinct Parasites 901
35.3 Pharmacodynamics 820
35.4 Conclusion 830 Federica Giordani, Roy Mwenechanya,
References 830 and Michael P. Barrett
39.1 Overview 901
36. Tuberculosis 835 39.2 The Genetics of Trypanosome Lytic
Factors and Parasite Factors Enabling
Geetha Ramachandran and
Protection Against Lysis 903
Soumya Swaminathan
39.3 Immune Responses and
36.1 Overview 835 Immunoavoidance 905
36.2 TB Etiology and Natural History 835 39.4 Pathologies Associated with Hat 906
36.3 Burden of TB 836 39.5 Diagnosis of Hat 907
36.4 Burden of TB Among Children 838 39.6 Staging the Disease 908
36.5 TB Diagnosis 838 39.7 Treatment 909
36.6 Chemotherapy for TB 840 39.8 Conclusions and Future Perspectives 913
36.7 Risk Factors: Genetics, HIV, Diabetes, Glossary 914
and Smoking 842 References 914
36.8 TB in Children 844
36.9 Pharmacogenomics of TB 845
36.10 Pharmacogenomics and TB 845 Part VIII
36.11 Conclusion 853
References 853 Implementation and Regulatory
37. Hepatitis C Virus 859 40. Implementing Clinical
A.J. Thompson, P. Clark, and A. Aghemo
Pharmacogenetics: Point-of-Care
and Pre-Emptive Testing 921
37.1 Overview 859
37.2 IL28B Polymorphism and HCV Outcomes 860 Stuart A. Scott
37.3 ITPA Polymorphisms and
Ribavirin-Induced Hemolytic Anemia 864 40.1 Overview 921
37.4 Genetic Determinants of Liver Fibrosis 40.2 Clinical Pharmacogenetics and
Progression 865 Implementation 922
37.5 Clinical Translation 866 40.3 Point-of-Care Pharmacogenetic
37.6 Conclusion 872 Testing 924
Acknowledgments 872 40.4 Pre-Emptive Pharmacogenetic
Disclosures 872 Testing 925
Abbreviations 872 40.5 Conclusion and Future Perspectives 927
References 873 References 928
Contents xiii

41. Ethical Considerations in Acronyms and Abbreviations 995

Pharmacogenomic Testing and References 996
Research in Pediatrics 931
44. Pharmacogenomics in China 999
Chi Dang Hornik, Cait O’Donnell,
and Raymond Barfield Wei Zhang, Hong-Hao Zhou, Zhao-Qian Liu,
Xiao-Ping Chen, and Yi-Jing He
41.1 Overview 931
41.2 Historical Perspective 933 44.1 Overview 999
44.2 Pharmacogenomics
41.3 Ethical Significance of Benefit, Risk,
of Drug-Metabolizing Enzymes
and Uncertainty in Pediatric
in Chinese Populations 999
Pharmacogenomics 935
44.3 Pharmacogenomics of Drug Transporters
41.4 Federal Regulations and National
in Chinese Populations 1002
Healthcare Priorities Related to
44.4 Pharmacogenomics of Drug Receptors
Pharmacogenomics 943
in Chinese Populations 1006
41.5 Translation of Pharmacogenomics into
44.5 Pharmacogenomics of ION Channels
the Clinical Setting 945
in Chinese Populations 1009
41.6 Future Implications of Pharmaco­genomics
44.6 Environmental Factors in Drug-
Testing in Children 946
Metabolizing Enzyme and Transporter
41.7 Conclusion 948
Activity 1011
References 948
44.7 Translational Approaches to
Pharmacogenomics in China 1012
42. PGx/Biomarker Utilization for 44.8 Conclusion and Future Perspectives 1012
Regulatory Decision Making 951 Acknowledgments 1012
References 1012
Yu Sakamoto, Yasuto Otsubo, Akihiro
Ishiguro, and Yoshiaki Uyama 45. Pharmacogenomics in Brazil 1015
42.1 Introduction 951
42.2 Regulatory Activities and Guidelines Guilherme Suarez-Kurtz and
Relating to PGx/Biomarker 951 Mara Helena Hutz
42.3 Biomarker Qualification 956 45.1 Overview 1015
42.4 Clinical Trial Design and Drug 45.2 The Brazilian Pharmacogenetics
Development Utilizing PGx/Biomarker 960 Network–Refargen 1015
42.5 Future Challenges 963 45.3 PGX of Immunosuppressants in Renal
Disclaimer 964 Transplant Patients 1028
Glossary 964 45.4 PGX of Antipsychotics in Schizophrenic
Acronyms and Abbreviations 964 Patients 1030
References 965 45.5 Conclusions 1032
Acknowledgments 1033
Part IX References 1033

Global Perspective 46. Pharmacogenomics in India 1037

43. Population Diversity and Umamaheswaran Gurusamy and
Pharmacogenomics in Africa 971 Deepak Gopal Shewade

Collen Masimirembwa, Collet Dandara, 46.1 Overview 1037

and Julia Hasler 46.2 Indian Population Structure and
Diversity 1038
43.1 Overview 971 46.3 Frequency Distribution and Pattern
43.2 Population Diversity in Africa 973 of Genetic Variants of Pharmacogenes 1039
43.3 Population Genetics, Diversity, Ancestry, 46.4 Pharmacogenetic Studies in India 1052
and Admixture 979 46.5 Conclusions and Future Directions 1056
43.4 Pharmacogenomics in Africa 985 References 1057
43.5 Future Perspectives 992
43.6 Conclusions 994
Key Concepts 994 Glossary 1061
Acknowledgments 995 Acronyms and Abbreviations 1065
Glossary 995 Index 1071
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