Table of Contents
Foreword . . . xxv
Preface . . . xxvii
Acknowledgements . . . xxix
Abbreviations . . . xxxi
Advisory Board . . . xxxix
Contributors . . . xli
PART I GENOMIC APPROACHES TO BIOLOGY AND MEDICINE
Section 1 Principles of Human Genomics . . . 3
1. Organization, Variation and Expression of the Human
Genome as a Foundation of Genomic and Personalized
Medicine . . . 4
Huntington F. Willard
Introduction . . . 4
The Human Genome . . . 6
Variation in the Human Genome . . . 9
Expression of the Human Genome . . . 11
Genes, Genomes and Disease . . . 13
From Genome to Personalized Medicine . . .15
Conclusion . . . 18
References . . . 18
Recommended Resources 21
2. Concepts of Population Genomics . . . 22
Mike E. Weale and David B. Goldstein
Introduction . . . 22
Important Concepts in Population Genomics . . . 22
Human Population Genomics . . . 26
Application of Population Genomics to Genomic Medicine . . . 28
Conclusions . . . 29
References . . . 30
Recommended Resources . . . 32
3. Genomic Approaches to Complex Disease . . .33
Desmond J. Smith and Aldons J. Lusis
Introduction . . . 33
Identifying Common and Rare Genomic Variations
in the Population . . . 33
Relating DNA Variation to Phenotypes . . 36
Integration of “Omic” Technologies with Genetics . . . 40
Conclusions and Prospects . . . 43
Acknowledgements . . . 43
References . . . 43
Recommended Resources . . . 46
4. Human Health and Disease: Interaction Between the
Genome and the Environment . . . 47
Kenneth Olden
Introduction . . . 47
Importance of the Environment . . .48
The Environmental Genome Project . . . 50
Problematic Nature of Gene–environment
Interaction Studies . . . 52
Polymorphism and Disease Susceptibility:
Case–control Studies . . . 53
Epigenetics and the Environment . . . 56
Conclusion . . . 57
Acknowledgements . . . 57
References . . . 57
5. Epigenomics and its Implications for Medicine . . . 60
Moshe Szyf
Introduction . . . 60
DNA Methylation Patterns . . . 61
Chromatin Modification . . . 63
DNA Methylation and Chromatin States
Co-operatively Determine the State of Activity
of Genes . . . 65
Epigenetics and Human Disease . . .67
Conclusions . . . 69
Acknowledgements . . . 70
References . . . 70
6. Systems Biology and the Emergence of Systems
Medicine . . . 74
Nathan D. Price, Lucas B. Edelman, Inyoul Lee,
Hyuntae Yoo, Daehee Hwang, George Carlson,
David J. Galas, James R. Heath and Leroy Hood
Introduction . . . 74
Systems Science in Biology And Medicine . . . 75
Multi-parameter Blood-bourne Biomarkers . . . 76
Emerging in vivo and in vitro Technologies . . . 78
Computational and Mathematical Challenges in
Systems Medicine . . . 81
Conclusions and Perspectives . . . 81
References . . . 82
Recommended Resources . . . 85
Section 2 Technology Platforms for Genomic Medicine . . . 87
7. DNA Sequencing for the Detection of Human
Genome Variation and Polymorphism . . . 88
Samuel Levy and Yu-Hui Rogers
Introduction . . . 88
DNA Sequencing . . . 89
Other Methodologies for Polymorphism Detection . . . 95
Future Directions . . . 96
Acknowledgements . . . 97
References . . . 97
8. Genome-Wide Association Studies and Genotyping
Technologies . . . 101
Kevin V. Shianna
Introduction . . . 101
Principles of Genome-wide Association Studies . . . 101
Platform Overview . . . 103
Conclusion . . . 106
References . . . 106
9. Copy Number Variation and Human Health . . . 108
Charles Lee, Courtney Hyland, Arthur S. Lee,
Shona Hislop and Chunhwa Ihm
Introduction . . . 108
Basic Principles of CNVs . . . 108
Detecting CNVs in a Genome-wide Manner . . . 112
Association of CNVs to Disease and Disease
Susceptibility . . . 114
Implications of CNVs . . . 116
Conclusions . . . 118
Acknowledgements . . . 118
References . . . 118
Recommended Resources . . . 119
10. Inter-Species Comparative Sequence Analysis: A Tool
for Genomic Medicine . . . 120
Anthony Antonellis and Eric D. Green
Introduction . . . 120
Performing Comparative Sequence Analysis:
Resources and Methods . . . 121
Comparative Sequence Analysis and Human
Genetic Disease . . . 124
CSA and the Future of Human Genetics and
Genomic Medicine . . . 128
References . . . 128
Recommended Resources . . . 130
11. DNA Methylation Analysis: Providing New Insight
into Human Disease . . . 131
Susan Cottrell, Theo deVos, Juergen Distler, Carolina
Haefliger, Ralf Lesche, Achim Plum and Matthias Schuster
Introduction . . . 131
Technology to Assess DNA Methylation . . . 132
Clinical Impact of DNA Methylation Analysis . . . 136
Conclusion . . .139
References . . . 139
Recommended Resources . . . 142
12. Transcriptomics: Translation of Global Expression
Analysis to Genomic Medicine . . . 143
Michelle M. Kittleson, Rafael Irizarry, Bettina Heidecker
and Joshua M. Hare
Introduction . . . 143
Gene Expression Technology . . . 143
Gene Discovery . . . 146
Molecular Signature Analysis . . . 148
Gene Discovery Versus Molecular Signature Analysis . . .151
Current Issues in Gene Expression Analysis . . . 151
Alternative Technologies for Analysis of the
Transcriptome . . . 153
Conclusion . . . 153
Acknowledgements . . . 154
References . . . 154
Recommended Resources . . . 156
13. DNA Microarrays in Biological Discovery and
Patient Care . . 157
Andrew J. Yee and Sridhar Ramaswamy
Introduction . . . 157
Microarray Technology . . . 157
Data Analysis . . . 160
Applications . . . 161
Limitations and Challenges . . . 165
Future Directions . . . 165
Conclusions . . . 168
References . . . 168
Recommended Resources . . . 172
14. Proteomics: The Deciphering of the Functional Genome . . . 173
Li-Rong Yu, Nicolas A. Stewart and Timothy D. Veenstra
Introduction . . . 173
Gel-based and Solution-based Proteomics . . . 174
Mass Spectrometry . . . 175
Bioinformatics . . . 176
Impact of Proteomics on Understanding Diseases . . . 178
Conclusions . . . 178
Acknowledgements . . . 179
References . . . 179
Recommended Resources . . . 179
15. Comprehensive Metabolic Analysis for
Understanding of Disease Mechanisms . . . 180
Christopher B. Newgard, Robert D. Stevens, Brett R. Wenner,
Shawn C. Burgess, Olga Ilkayeva, Michael J. Muehlbauer,
A. Dean Sherry and James R. Bain
Introduction . . . 180
Current Metabolomics Platforms: Basic Tools and
General Features . . . 181
Comparison of NMR and MS Technologies for
Unbiased Metabolic Profiling . . . 182
MS Methods for Targeted Metabolic Profiling . . . 183
Examples of NMR-based Metabolic Profiling in
Disease Research . . . 184
Examples of Targeted MS-based Metabolic Profiling
for Understanding of Disease Mechanisms . . . 184
Integration of Metabolic Profiling with Other
“Omics” Technologies . . . 189
Future Directions . . . 189
References . . . 190
16. Comprehensive Analysis of Gene Function: RNA
interference and Chemical Genomics . . . 193
Bjorn T. Gjertsen and James B. Lorens
Introduction . . . 193
RNA Interference . . . 194
Gene Function Analysis: An Overview . . . 194
Chemical Genomics . . . 197
Gene Function Studies . . . 199
Conclusions . . . 200
Acknowledgements . . . 201
References . . . 201
Recommended Resources . . . 203
Section 3 Informatic and Computational Platforms for Genomic Medicine . . . 205
17. Bioinformatic and Computational Analysis for
Genomic Medicine . . . 206
Atul J. Butte
Introduction . . . 206
Vignettes: How Specific Bioinformatics Methods
Can Change the Practice Of Medicine . . . 207
Analytic Methods . . . 213
Where Data for Studies May be Found . . . 214
Bioinformatics Vocabularies and Ontologies . . . 215
Freely Available Bioinformatics Tools . . . 216
New Questions for Genomic Medicine . . . 220
Acknowledgements . . . 221
References . . . 221
Recommend Resources . . . 225
18. Fundamentals and History of Informatics for
Genomic and Personalized Medicine . . 226
A. Jamie Cuticchia
Introduction . . . 226
Databases for Genomic Medicine . . . 227
Conclusion . . . 230
References . . . 231
Recommended Resources . . . 232
19. Electronic Medical Records in Genomic Medicine
Practice and Research . . . 233
Glenn S. Gerhard, Robert D. Langer, David J. Carey
and Walter F. Stewart
Introduction . . . 233
EMRs and Genomic Medicine Clinical Practice . . . 234
EMRs and Genomic Medicine Research . . . 236
Conclusion . . . 240
Acknowledgements . . . 240
References . . . 240
Recommended Resources . . . 241
20. Clinical Decision Support in Genomic and
Personalized Medicine . . . 242
Kensaku Kawamoto and David F. Lobach
Introduction . . . 242
CDS Background: History, Examples, Evidence of
Effectiveness, and Desirable Attributes . . . 243
Potential Uses of CDS to Support Genomic and
Personalized Medicine . . . 245
Limited Deployability: The Potential Achilles' Heel
of CDS Systems for Genomic Medicine . . . 246
Challenges to Widespread Deployment of Effective
CDS Systems . . . 247
Conclusions . . . 249
Disclosures . . . 249
References . . . 249
Recommended Resources . . . 251
21. Online Health Information Retrieval by Consumers
and the Challenge of Personal Genomics . . . 252
Mark S. Boguski
Introduction . . . 252
Characteristics of Consumer Searches for Health
Information . . . 252
What and Where Are Consumers Searching? . . . 253
Personalized Genomics for Consumers . . . 255
Summary and Conclusions . . . 256
References . . . 256
Wikipedia References . . . 257
PART II TRANSLATIONAL APPROACHES IN GENOMIC AND PERSONALIZED MEDICINE
Section 4 Enabling Strategies in the Translation of Genomics into Medicine . . . 261
22. Translational Genomics: From Discovery to Clinical
Practice . . . 262
Geoffrey S. Ginsburg
Introduction . . . 262
A Roadmap for Translation . . . 263
Where Can Genomics Have Impact in the
Continuum of Health and Disease? . . . 263
The Genomics “Gold Rush” . . . 264
The Personal Genome: Precious Code or Fool’s Gold? . . . 266
“Grand Challenges” in Translation of Genomics to
Human Health . . . 266
Translational Genomics: Enabling
Competencies . . . 267
How Are We Going to Do This? Developing
Environments That Foster Translational Genomics
to Health Applications . . . 270
References . . . 272
23. Principles of Study Design . . . 275
Peter Grass
Introduction . . . 275
Principles of Experimental Design . . . 276
Design Issues in Genomic Medicine . . . 281
References . . . 283
Recommended Resources . . . 283
24. Biobanking in the Post-Genome Era . . . 284
Theresa Puifun Chow, Chia Kee Seng, Per Hall and
Edison T. Liu
Introduction . . . 284
The Biobanking Evolution . . . 285
The Past Imperfect Resources . . . 285
The Evolving Face of Biobanking . . . 285
Existing Models: Biobanking in Europe and the USA . . . 286
Singapore’s National Biobank and National
Aspirations In Biomedical Research . . . 288
The Future of National Biobanks . . . 294
References . . . 296
Recommended Resources . . . 297
25. Application of Biomarkers in Human Population
Studies . . . 299
Stefano Bonassi and Monica Neri
Introduction . . . 299
Biomarkers in Medicine . . . 299
Biomarkers of Exposure . . . 302
Biomarkers of Early Disease Risk . . . 303
Biomarkers of Genetic Susceptibility to Disease . . . 304
Conclusions . . . 306
References . . . 306
26. Validation of Candidate Protein Biomarkers . . . 308
Ingibjörg Hilmarsdóttir and Nader Rifai
Introduction . . . 308
Optimization of the Candidate Protein Research Assay . . . 308
Analytical Evaluation . . . 309
Reference Intervals . . . 311
Pre-analytical Variation . . . 311
Clinical Evaluation . . . 312
Indicators of Diagnostic Accuracy And Predictability . . . 313
Diagnostic Research Studies . . . 316
Design of Diagnostic Studies . . . 316
Transferability Of Test Performance . . . 317
Assay Transfer to Diagnostic Company . . . 317
Regulatory Requirements . . . 318
References . . . 318
Recommended Resources . . . 320
27. Pharmacogenetics and Pharmacogenomics . . . 321
Iris Grossman and David B. Goldstein
Introduction . . . 321
Pharmacogenetic Studies: From Concept to Practice . . . 323
Marker Selection – Strategy and Application . . . 325
From Bench to Bedside: Integration of
Pharmacogenetic Testing into Clinical Practice . . . 328
Examples of PGx Tests: Promising New Developments
and Marketed Products . . . 329
Future Developments Required for the Field to
Fully Meet its Expectations . . . 331
References . . . 332
Recommended Resources . . . 334
28. The Role of Genomics and Genetics in Drug
Discovery and Development . . . 335
Robert I. Tepper and Ronenn Roubenoff
Introduction . . . 335
The Drug Discovery Process . . . 335
Genomics in Target Discovery . . . 336
Genomic Approaches to Drug Identification . . . 337
Pharmacogenomics and Drug Development . . . 337
Pharmacodynamic Markers and their Role in Drug
Discovery and Development . . . 338
Toxicogenomics . . . 340
Genetics and Genomics in Clinical Trial Design . . . 340
Genomics in Drug Approval and Regulation . . . 340
Conclusion . . . 341
References . . . 341
Recommended Resources . . . 342
29. Role of Pharmacogenomics in Drug Development . . . 343
Colin F. Spraggs, Beena T. Koshy, Mark R. Edbrooke
and Allen D. Roses
Introduction . . . 343
Drug Development Critical Path . . . 344
Drug Development Economics . . . 344
Methods for Identifi cation of Genetic Classifiers . . . 344
Pharmacogenomics in the Drug Development Pipeline . . . 346
Efficacy Pharmacogenetics – here and Now . . .348
Drug Exposure Pharmacogenetics to Tune Efficacy
and Safety Profiles . . . 349
Investigation and Management of Safety in Clinical Trials . . . 350
Other Genomic Methods: RNA Interference to
Direct Drug Usage . . . 352
“No Samples, No Science” . . . 352
Conclusions . . . 354
Acknowledgements . . . 355
References . . . 355
30. Clinical Implementation of Translational Genomics . . . 357
Wendy K. Chung
Introduction . . . 357
Genetic Stratifi cation Will Allow Medical Care to be
Individualized After a Diagnosis is Made . . . 357
Population-based Germline Genomic Screening . . . 358
Newborn Screening . . . 359
Pharmacogenetics . . . 360
Somatic Genomic Variation . . . 360
Novel Sources of Genomic Variation . . . 361
Laboratory Standards to Ensure Analytic Validity . . . 361
Clinical Validation and Clinical Utility . . . 362
Cost . . . 362
Reimbursement . . . 363
Who Will Provide Genomic Medical Care? . . . 363
Genomic Literacy . . . 364
Ethical, Legal, and Social Issues . . . 364
Conclusions . . . 365
Acknowledgements . . . 365
References . . . 365
Recommended Resources . . . 366
31. Translating Innovation in Diagnostics: Challenges
and Opportunities . . . 367
Matthew P. Brown, Myla Lai-Goldman and
Paul R. Billings
Introduction . . . 367
Novel Diagnostics . . . 368
Conclusions: Translational Challenges for Innovative
Diagnostics . . . 374
References . . . 375
32. The Role of Genomics in Enabling Prospective
Health Care . . . 378
Ralph Snyderman
Introduction . . . 378
Predictive Models . . . 380
Predictive Factors . . . 380
Risk Assessment for Breast Cancer . . . 382
Pharmacogenomics . . . 383
Conclusion . . . 383
Acknowledgements . . . 383
References . . . 384
Recommended Resources . . . 385
Section 5 Policy Challenges in Genomic and Personalized Medicine . . . 387
33. From Sequence to Genomic Medicine: Genome
Policy Considerations . . . 388
Susanne B. Haga
Introduction . . . 388
Genome Research after the Human Genome Project . . . 389
Policy Issues in Large-scale Genetics and Genomics
Research . . . 391
Integrating Genomic Medicine Applications in
Healthcare . . . 392
Conclusion . . . 396
References . . . 397
34. Educational Strategies in Genomic Medicine . . . 401
Charles J. Epstein
Introduction . . . 401
Genetic and Genomic Literacy of the Public and
Makers of Public Policy . . . 402
Education of the Providers of Health Care . . . 404
Conclusion . . . 411
References . . . 411
35. Federal Regulation of Genomic Medicine . . . 414
Janet Woodcock
Introduction . . . 414
Regulation of Genomic Tests . . . 416
Pharmacogenomics in Drug Development And
Clinical Medicine: the Role of Regulation . . . 418
FDA Efforts to Advance Genomic Product
Development . . . 421
Conclusions . . . 422
References . . .422
Recommended Resources . . . 423
36. Economic Issues and Genomic Medicine . . . 424
David L. Veenstra, Louis P. Garrison and Scott D. Ramsey
Introduction . . . 424
Economic Evaluation and Cost-effectiveness Analysis . . . 424
Evaluating Genomic Technologies . .. 426
Economic Incentives and the Future of Genomic
Medicine . . . 428
Establishing Value-based Reimbursement For
Genomic Technologies . . . 430
Conclusions . . . 431
References . . . 432
37. Public–Private Interactions in Genomic Medicine:
Research and Development . . . 434
Subhashini Chandrasekharan, Noah C. Perin,
Ilse R. Wiechers and Robert Cook-Deegan
Introduction . . . 434
Landscape of Private Sector Genomics . . . 435
Future Trends . . . 441
Acknowledgements . . . 442
References . . . 442
Section 6 Genomic Medicine and Public Health . . . 445
38. What Is Public Health Genomics? 446
Alison Stewart and Ron Zimmern
Introduction . . . 446
The Emergence of Public Health Genomics . . . 446
The Definition of Public Health Genomics . . . 447
Key Concepts in Public Health Genomics . . . 447
The “Enterprise” of Public Health Genomics . . . 448
Core Activities in Public Health Genomics . . . 449
Moving Public Health Genomics Forward:
Leadership And Networks . . . 451
Conclusion . . . 452
References . . . 452
Recommended Resources . . . 453
39. Why Do We Need Public Health in the Era of
Genomic Medicine? 454
Muin J. Khoury and Marta Gwinn
Introduction . . . 454
The Continuum from Genetics to Genomics in
Health Practice . . . 454
The Role of Public Health in the Translation of
Human Genome Discoveries into Health
Applications . . . 455
The Focus on Disease Prevention and Health
Promotion . . . 457
The Population Perspective: Crucial Role of Public
Health Sciences . . . 457
The Role of Knowledge Integration Across
Disciplines . . . 458
The Role of Health Services Research and Population
Health Assessment, Assurance, and Evaluation . . . .458
Conclusion . . . 458
References . . . 459
40. Principles of Human Genome Epidemiology . . . 461
Marta Gwinn and Muin J. Khoury
Introduction . . . 461
Human Genome Epidemiology . . . 461
Epidemiologic Study Designs . . . 462
Epidemiologic Measures Of Disease Frequency,
Association, and Risk . . . 463
Measurement and Bias . . . 464
Gene–environment Interaction . . . 465
Probability and Personalized Medicine . . . 466
Building the Evidence Base . . . 466
Conclusion . . . 467
References . . . 467
Recommended Resources . . . .469
41. Genomics and Population Screening: Example of
Newborn Screening . . . 470
John D. Thompson and Michael Glass
Introduction . . . 470
Components of the NBS System . . . 471
Screening Technology: Simple Ideas, Complex
Realities . . . 471
Variability Among NBS Programs . . . 476
Influence of Genetics and -omic Technologies
on NBS . . . 476
Acknowledgements . . . 477
References . . . 477
Recommended Resources . . . 479
42. Family History: A Bridge Between Genomic
Medicine and Disease Prevention . . . 481
Maren T. Scheuner and Paula W. Yoon
Introduction . . . 481
Clinical Approach . . . 481
Conclusion . . . 488
Acknowledgements . . . 488
References . . . 488
Recommended Resources . . . 492
Section 7 Clinical Technologies Supporting Personalized Medicine . . . 493
43. Molecular Imaging as a Paradigm for Genomic and
Personalized Medicine . . . 494
Ralph Weissleder
Introduction . . . 494
Molecular Imaging and Cancer Detection . . . 494
Molecular Imaging to Determine Treatment Efficacy . . . 496
Molecular Imaging and Drug Development . . . 497
Near-term Needs and Opportunities . . . 497
Acknowledgement . . . 498
References . . . 498
44. PET Imaging in Genomic Medicine . . . 500
Vikas Kundra and Osama Mawlawi
Introduction . . . 500
Physics . . . 500
Imaging Agents and Methods in Analysis of
Biological Samples . . . 503
Conclusion . . . 510
References . . . 510
Recommended Resources . . . 511
45. MRI for Molecular Imaging Applications:
Overview, Perspectives, and Challenges 512
Dmitri Artemov
Introduction . . . 512
Basics of MRI Contrast . . . 513
MR Contrast Agents for Molecular Imaging
Applications . . . 515
Molecular Imaging Applications of MRI . . . 517
Conclusions . . . 520
Acknowledgements . . .521
References . . . 521
46. Fluorescence Imaging: Overview and Applications
in Biomedical Research . . . 524
Vasilis Ntziachristos
Introduction . . . 524
Imaging Technology . . . 525
Fluorescence Applications in Genomic Medicine . . . 530
References . . . 530
47. Imaging Genetics: Integration of Neuroimaging and
Genetics in the Search for Predictive Markers . . . 532
Ahmad R. Hariri
Introduction . . . 532
Conceptual Basis of Imaging Genetics . . . 533
Basic Principles of Imaging Genetics . . . 534
Imaging Genetics and the Neurobiology of the
5-httlpr . . . 535
Future Directions . . . 536
References . . .536
48. Viral Chip Technology in Genomic Medicine . . . 538
Zeno Földes-Papp
Introduction . . . 538
Role of Viruses in Human Infectious Disease . . . 538
Microfabrication . . . 541
Nanofabrication . . . 552
Are there Additional Alternatives to Diagnostic
Microarrays? . . . 553
Conclusions . . . 554
Acknowledgements . . . 554
References . . .554
Recommended Resources . . . 560
49. Vaccines Against Infectious Diseases: A
Biotechnology-Driven Evolution . . . 562
Vega Masignani, Hervé Tettelin and Rino Rappuoli
Introduction . . . 562
The Genomic Era: From Microbial Genome to
Vaccine Development . . . 563
Impact of Whole Genome Analyses . . . 564
In Vivo Gene Expression: Ivet And Stm . . . 566
Microarray Expression Technology . . . 567
Proteomics . . . 568
From Microbial to Human Genome Sequencing:
Genomic Medicine . . . 568
Metagenomics: Deciphering Host–microbe
Interactions . . . 569
Conclusions . . . 570
References . . . 570
50. Cancer Vaccines: Some Basic Considerations . . . 573
Hans-Georg Rammensee, Harpreet Singh-Jasuja, Niels
Emmerich and Steve Pascolo
Introduction . . . 573
Immune Suppression by Tumors and by Regulatory
T-cells . . . 574
The Ideal Therapeuticcancer Vaccine . . . 576
Molecularly Undefi nedcancer Vaccines . . . 576
Peptides . . . 577
Proteins and Carbohydrates . . . 578
Nucleic Acids: Plasmid DNA and Messenger
RNA . . . 579
Viral and Bacterial Vectors . . . 582
Adjuvants, Formulations, and Route of Application . . . 582
Immunomonitoring . . . 583
Conclusions . . . 584
References . . . 584
51. Biosensors for the Genomic Age . . . 590
Meghan B. O’Donoghue, Lin Wang, Yan Chen, Gang Yao
and Weihong Tan
Introduction . . . 590
Biosensors for Detection of Oligonucleotides for the
Detection of Disease . . . 591
Nucleic Acid as Tools for Biosensing . . . 592
Outlook . . . 596
References . . . 597
52. Stem Cells . . . 599
Rikkert L. Snoeckx, Kris Van Den Bogaert and Catherine
M. Verfaillie
Introduction . . . 599
Types of Stem Cells: Embryonic and Adult Stem Cells . . . 599
How to Defi ne The Molecular Signature of Stem Cells . . . 600
Future Directions to Identify the Global Integrated
Regulatory Network . . . 601
Future Directions in Stemcell Therapies . . . 604
Conclusion . . . 606
References . . . 606
53. Gene Therapy . . . 610
James M. Wilson and Nelson A. Wivel
Introduction . . . 610
Gene Delivery Vehicles . . . 611
Gene Therapy Clinical Trials . . . 614
Conclusion . . . 617
References . . . 617
PART III DISEASE-BASED GENOMIC AND PERSONALIZED MEDICINE: GENOME DISCOVERIES AND CLINICAL APPLICATIONS
Section 8 Cardiovascular Genomic Medicine . . . 623
54. The Genomics of Hypertension . . . 624
Chana Yagil and Yoram Yagil
Introduction . . . 624
Predisposition . . . 625
Screening . . . 627
Diagnosis . . . 627
Prognosis . . . 628
Pharmacogenomics . . . 630
Monitoring . . . 631
Novel and Emerging Therapeutics . . . 631
Conclusion . . . 631
Acknowledgements . . . 632
References . . . 632
Recommended Resources . . . 633
55. Lipoprotein Disorders . . . 634
Sekar Kathiresan and Daniel J. Rader
Introduction . . . 634
Overview of Lipoprotein Metabolism . . . 634
Plasma Lipid and Lipoprotein Levels and
Atherosclerotic Cardiovascular Disease . . . 636
Inherited Basis for Blood Lipid Traits . . . 636
Screening for Lipid Disorders . . . 637
Genetics of Ldl-c . . . 637
Genetics of Hdl-c . . . 639
Genetics of Triglycerides . . . 642
Genetic Lipid Disorders Without Current Proven
Molecular Etiology . . . 643
Infl uence of Lipid-modulating Mutations on Risk
of Atherosclerotic Cardiovascular Disease . . . 643
Future Directions in Genetics And Genomics of
Lipoproteins . . . 644
Pharmacogenetics of Lipid-modulating Therapies . . . 646
Implications of Genomics of Lipoprotein Metabolism
For The Development of Novel Therapies . . . 646
Clinical Recommendations for Genetic Testing for
Lipid Disorders . . . 647
Acknowledgements . . . 648
References . . . 648
Recommended Resources . . . 651
56. Reactive Oxygen Species Signals Leading to Vascular
Dysfunction and Atherosclerosis . . . 652
Nageswara R. Madamanchi, Aleksandr E. Vendrov and
Marschall S. Runge
Introduction . . . 652
Sources of ROS in vascular cells . . . 652
Vascular Dysfunction and Atherosclerosis . . . 653
ROS-induced infl ammatory gene expression in
vascular cells . . . 653
Association of ROS modulators with atherosclerosis . . . 654
ROS signaling in atherosclerotic risk factors . . . 655
ROS-regulated signaling pathways . . . 655
Regulation of transcription factors by ROS . . . 656
ROS signaling in advanced atherosclerosis . . . 658
Polymorphisms in ROS production genes and
atherosclerosis . . . 658
Inhibitors of ROS signaling and vascular disease . . . 658
Conclusion . . . 659
Acknowledgements . . . 660
References . . . 660
57. Genomics of Myocardial Infarction . . . 665
Carlos A. Hubbard and Eric J. Topol
Introduction . . . 665
Predisposition . . . 665
Screening Strategies . . . 672
Diagnosis of Acute MI . . . 673
Prognostic Implications of MI . . . 673
Pharmacogenomics of MI . . . 673
Novel and Emerging Therapies . . . 674
Conclusion . . . 675
References . . . 676
Recommended Resources . . . 679
58. Acute Coronary Syndromes . . . 680
L. Kristin Newby
Introduction . . . 680
Predisposition . . . 680
Screening . . . 681
Diagnosis . . . 682
Prognosis . . . 685
Pharmacogenomics . . . 686
Monitoring . . . 687
Novel and Emerging Therapeutics . . . 687
Conclusion . . . 687
Acknowledgements . . . 687
References . . . 688
Recommended Resources . . . 690
59. Heart Failure in the Era of Genomic Medicine . . . 692
Ivor J. Benjamin and Jeetendra Patel
Introduction . . . 692
Predisposition (Genetic and Non-genetic) . . . 692
Screening . . . 693
Pathophysiology . . . 694
Diagnosis . . . 695
Prognosis . . . 696
Pharmacogenomics . . . 697
Monitoring . . . 698
Novel Therapeutics and Future Directions . . . 701
Conclusions and Recommendations . . . 702
Acknowledgements . . . 703
References . . . 703
60. Application of Genomic Methodology for Assessment
of Cardiac Transplant Rejection . . . 705
Michael Pham, Mario C. Deng, Jay Wohlgemuth and
Thomas Quertermous
Introduction . . . 705
Cardiac Allotransplantation as a Definitive Therapy
for End-stage Heart Failure . . . 705
The Problem of Allograft Rejection . . . 706
Immunosuppression Strategies to Prevent Rejection . . . 706
Current Strategies for Monitoring Transplant
Rejection . . . 707
The Cargo Clinical Study . . . 709
Development of a Gene Expression Signature
For Cardiac Transplant Rejection . . . 709
Pathways Monitored by the Gep (Allomap™) Test . . . 710
Variability of the Biopsy Gold Standard and
Relationship to the Gep (Allomap™) Score . . . 710
Discordance Between Biopsy Grade and Molecular
Score . . . 710
Effect of Time Post-transplantation on Performance
of the Gep Test . . . 711
Relationship of Gep Score to Corticosteroid Dose . . . 711
Relationship of Gep Scores to Cytomegalovirus
Infection . . . 711
Prediction of Future Acr by Molecular Score . . . 712
Clinical Use of the Allomap™ Test . . . 712
Future Directions and Ongoing Research With Gep
Testing . . . 713
Further Application of Genomic Science to
Transplant Rejection . . . 713
References . . . 714
61. Hypertrophic Cardiomyopathy in the Era of
Genomic Medicine . . . 716
J. Martijn Bos, Steve R. Ommen and Michael J. Ackerman
Introduction . . . 716
Definitions, Clinical Presentation, and Diagnosis . . . 716
Molecular Genetics of HCM . . . 718
Screening And Treatment for HCM . . . 722
Conclusions . . . 725
References . . . 725
62. Genetics and Genomics of Arrhythmias . . . 729
Jeffrey A. Towbin and Matte Vatta
Introduction . . . 729
Specifi c Cardiac Arrhythmias . . . 729
Primary Abnormalities in Cardiac Rhythm:
Ventricular Tachyarrhythmias . . . 729
Complex Forms of Lqts . . . 736
Short Qt Interval Syndrome . . . 741
Familial Vt/cpvt . . . 741
Primary Conduction Abnormalities . . . 742
References . . . 745
63. Hemostasis and Thrombosis . . . 755
Richard C. Becker and Felicita Andreotti
Introduction . . . 755
Genetics of Coagulation . . . 755
Human Hemostatic Variability . . . 756
Genotype–phenotype Influences . . . 757
Gene-environment Influences on Hemostasis . . . 758
Circulating Cellular and Protein Influences on
Hemostasis And Thrombosis . . . 759
Race-related Infl uences On Hemostasis and
Thrombosis . . . 760
Linkage Studies in Thrombosis . . . 762
Association Studies in Thrombosis . . . 762
Heritability And Thrombosis: Existing Complexities . . . 763
A Personalized Approach to Hemostasis and
Thrombosis . . . 763
Patient Screening: A Traditional Paradigm . . . 764
Patient Screening: A Comprehensive And
Population-based Approach . . . 767
Prognostic Considerations . . . 768
Emerging Platform for Hemostasis and Thrombosis
Research . . . 768
References . . . 769
64. Peripheral Arterial Disease . . . 773
Ayotunde O. Dokun and Brian H. Annex
Introduction . . . 773
Epidemiology and Risk Factors for PAD . . . 773
Clinical Manifestations of PAD . . . 773
Therapeutic Strategies for PAD . . . 774
Ic And Cli Are Distinct Clinical Outcomes of PAD . . . 775
Genetic Background as a Risk Factor for PAD . . . 775
Gene Polymorphisms Contributing to Atherosclerosis
and PAD . . . 775
Polymorphisms in Pro-atherothrombotic Genes and
PAD . . . 776
Genetic Locus Conferring Susceptibility to PAD . . . 776
Identifi cation of Novel Gene Polymorphisms
Involved in PAD . . . 776
Identifi cation of a Quantitative Trait in a
Preclinical Model of PAD . . . 777
Refi ning a QTL Using Haplotype Analysis . . . 777
Identifi cation of Candidate Genes . . . 777
Future Potential Use of Genomic Methodologies in PAD . . . 777
Acknowledgements . . . 778
References . . . 778
65. Genomics of Congenital Heart Disease . . . 781
Jessie H. Conta and Roger E. Breitbart
Introduction . . . 781
CHD Gene Discovery by Conventional Genetics . . . 781
Genomic Strategies for CHD Gene Discovery . . . 786
Cytogenetic and Molecular Genetic testing . . . 787
Medical Evaluation and Counseling Recommendations . . . 788
Conclusion . . .789
Acknowledgements . . . 790
References . . . 790
Recommended Resources . . . 793
66. Genomics of Perioperative and Procedural Medicine . . . 794
Simon C. Body, Mihai V. Podgoreanu and Debra A. Schwinn
Introduction . . . 794
Why Perioperative Insults are not Equivalent to
Chronic Ambulatory Disease . . . 795
Perioperative Atrial Fibrillation . . .796
Perioperative Venous and Arterial Thrombosis . . . 796
Perioperative Stroke and Neurocognitive Dysfunction . . . 798
Hemorrhage and Cardiac Surgery . . . 799
Dynamic Genomic Markers of Perioperative Outcomes . . . 799
Conclusion . . . 800
References . . . 800
Section 9 Oncology Genomic Medicine . . . 807
67. Cancer Genes, Genomes, and the Environment 808
Robert L. Strausberg
Introduction . . . 808
Acquired Functions of Cancer Cells . . . 808
Chromosomal Aberrations and Cancer . . . 808
Cancer Genes and their Functions . . . 809
Inherited Predisposition . . . 809
Cellular Progression Toward Cancer Through
Somatic Changes . . . 810
From Genome to the Clinic . . . 811
Comprehensive Sequencing of the Kinome . . . 811
Expanding the Search . . . 812
Multiple Molecular Mechanisms for Oncogene
Activation . . . 812
Microarrays and Cancer Genomics . . . 813
Environmental Cancer Genomics . . .813
Cancer Genomic Databases Expedite Progress . . . 813
Mouse Models of Cancer . . . 814
Future Directions . . . 814
References . . . 815
68. Immune Cells and the Tumor Microenvironment . . . 818
David S. Hsu, Michael Morse, Timothy Clay,
Gayathri Devi and H. Kim Lyerly
Introduction . . . 818
Immune Cells of the Tumor Microenvironment . . . 819
Examples of Tissue or Gene Microarrays
used to Study Tumors . . . 822
Studies of Genomic Immune Stimulation within the
Microenvironment . . . 823
Genomic Analysis of Tumor Microenvironment in
Immunotherapy Studies . . . 824
Proteomics of Immune Cells and the Tumor
Microenvironment . . . 825
Conclusion . . . 825
References . . . 826
69. Lymphomas . . . 830
Lisa Rimsza
Introduction . . . 830
Diffuse Large B-cell Lymphoma . . . 833
Primary Mediastinal Large B-cell Lymphoma . . . 835
Hodgkin Lymphoma . . . 835
Follicular Lymphoma . . . 836
Mantle Cell Lymphoma . . . 838
Burkitt Lymphoma . . . 839
Miscellaneous Lymphomas . . . 839
Clinical Applications of Molecular Assays in
Lymphoma . . . 840
References . . . 840
70. Genomics in Leukemias . . . 844
Lars Bullinger, Hartmut Dohner and Jonathan R. Pollack
Introduction . . . 844
Genomics in Leukemias-insights into Leukemia
Biology . . . 846
Genomics in Leukemias – Evaluation of Drug Effects . . . 847
Genomics in Leukemias – Clinical Outcome
Prediction . . . 849
Conclusions . . . 851
Acknowledgments . . . 852
References . . . 852
Recommended Resources . . . 855
71. Genomics of Lung Cancer . . .856
Hasmeena Kathuria, Avrum Spira and Jerome Brody
Introduction . . . 856
Early Diagnosis/screening of Lung Cancer . . . 857
Classifi cation And Prognosis . . . 859
Pathogenesis And Treatment of Lung Cancer . . . 862
Conclusion . . . 865
References . . . 866
Recommended Resource . . . 868
72. Breast Cancer and Genomic Medicine . . . 869
Erich S. Huang and Andrew T. Huang
Introduction . . . 869
The Promise . . . 869
Genetic Bases . . .871
Molecular Bases . . . 871
Prognosis and Prediction . . . 872
Molecular Markers . . .872
Genomic Insights . . .873
Netherlands Cancer Institute Study . . . 873
Duke-taipei Study . . .875
Nsabp Study . . . 875
Pathway Prediction . . . 876
The Reality of Clinical Genomics . . . 876
References . . . 877
73. Colorectal Cancer . . . 879
G.L. Wiesner, T.P. Slavin and J.S. Barnholtz-Sloan
Introduction . . . 879
Genomic Model of CRC . . . 880
Predisposition for CRC . . . 882
Risk Assessment, Evaluation, and Genetic Testing . . . 887
Screening and Surveillance . . . 889
Prognosis and Treatment . . . 889
Pharmacogenetics/genomics of Chemoprevention
and Chemotherapy . . . 890
Novel and Emerging Therapeutics . . . 892
Conclusion . . . 892
References . . . 893
74. Prostate Cancer . . . 898
Phillip G. Febbo and Philip W. Kantoff
Introduction . . . 898
Genetic Predisposition and Alterations in Prostate
Cancer . . . 898
Prostate Cancer Detection . . . 901
Genomic Changes Associated with Prostate Cancer
Behavior . . . 904
Genomic Changes associated with Hormone-Refractory Prostate Cancer . . . 906
Future Prospects of Genomics in Prostate Cancer
Care . . . 907
References . . . 908
75. Molecular Biology of Ovarian Cancer . . . 913
Tanja Pejovic, Matthew L. Anderson and Kunle Odunsi
Introduction . . . 913
Inherited Ovarian Cancer Syndromes . . . 913
Options for Screening and Prevention . . . 914
Genomic Instability and Ovarian Cancer . . . 914
Fanconi/anemia Pathway . . . 914
Somatic Mutations in Ovarian Cancer . . . 915
Oncogenes and Growth Factors . . . 916
Tumor Suppressor Genes . . . 917
Epigenetics in Ovarian Carcinogenesis . . . 917
Ovarian Cancer Metastases . . . 917
Angiogenesis . . . 918
Summary . . . 919
References . . . 919
76. Pancreatic Neoplasms . . . 921
Asif Khalid and Kevin McGrath
Introduction . . . 921
Predisposition (Genetic and Non-Genetic) . . . 922
Screening . . . 922
Diagnosis . . . 923
Prognosis . . . 926
Pharmacogenomics . . . 927
Monitoring . . . 927
Novel and Emerging Therapies . . . 927
Conclusion . . . 927
References . . . 928
77. The Multiple Endocrine Neoplasia Syndromes . . . 931
Y. Nancy You, Vipul Lakhani and Samuel A. Wells
Introduction . . . 931
The Multiple Endocrine Neoplasia Syndromes . . . 932
Conclusion . . . 941
Acknowledgements . . . 941
References . . . 942
Recommended Resources . . . 944
78. Genomics of Head and Neck Cancer . . . 945
Giovana R. Thomas and Yelizaveta Shnayder
Introduction . . . 945
Head and Neck Squamous Cell Carcinoma . . . 945
Conclusion . . . 952
References . . . 953
Recommended Resources . . . 955
79. Genomic Medicine, Brain Tumors and Gliomas . . . 956
Sean E. Lawler and E. Antonio Chiocca
Introduction . . . 956
Predisposition . . . 957
Screening . . . 958
Diagnosis and Prognosis . . . 958
Pharmacogenomics . . . 961
Monitoring . . . 962
Novel and Emerging Therapeutics . . . 962
Conclusions . . . 963
References . . . 964
80. Molecular Therapeutics of Melanoma . . . 967
Jiaqi Shi, Yonmei Feng, Robert S. Krouse, Stanely Leong
and Mark A. Nelson
Introduction . . . 967
Diagnosis . . . 967
Genetics of Melanoma . . . 968
Pharmacogenomics . . . 969
Novel and Emerging Therapeutics . . . 969
Conclusions . . . 973
References . . . 973
81. Emerging Concepts in Metastasis . . . 977
Nigel P.S. Crawford and Kent W. Hunter
Introduction . . . 977
Tools to Investigate the Mechanisms of Metastasis . . . 979
Assessement of Prognosis and New Treatments for
Metastasis: the Role of New Technologies 986
Conclusion . . . 987
References . . . 988
Recommended Resources . . . 989
82. Diagnostic-Therapeutic Combinations in the
Treatment of Cancer . . . 990
Jeffrey S. Ross
Introduction . . . 990
Targeted Therapies for Cancer . . 990
The Ideal Target . . .990
The First Diagnostic-therapeutic Combination in Cancer Therapy: Hormonal Therapy for Breast
Cancer . . . 992
Diagnostic-therapeutic Combinations for Leukemia
and Lymphoma . . . 994
Her-2 Positive Breast Cancer and Trastuzumab
(Herceptin®) . . . 994
Other Targeted Anticancer Therapies Using Antibodies . . . 995
Selected Targeted Anticancer Therapies Using Small
Molecules . . . 999
Pharmacogenomics . . . 1002
Conclusion . . . 1003
References . . . 1003
Section 10 Inflammatory Disease Genomic Medicine . . . 1009
83. Environmental Exposures and the Emerging Field
of Environmental Genomics . . . 1010
David A. Schwartz
Introduction . . . 1010
Importance of Environmental Exposures in Human
Health . . . 1010
Importance of Environmental Exposures in Studying
Disease Processes . . . 1012
Comparative Environmental Genomics . . . 1012
Exposure Assessment in the Gene-environment
Paradigm . . . 1013
Challenges and Future of Environmental Genomics . . . 1015
Conclusion . . . 1015
References . . . 1015
84. Molecular Basis of Rheumatoid Arthritis . . . 1017
Robert M. Plenge and Michael E. Weinblatt
Introduction . . . 1017
Clinical Features . . . 1018
Predisposition . . . 1018
Screening . . . 1024
Diagnosis, Prognosis, and Monitoring . . . 1024
Pharmacogenomics . . . 1024
Conclusions . . . 1026
References . . . 1026
85. “Omics” in the Study of Multiple Sclerosis . . . 1032
Francisco J. Quintana and Howard L. Weiner
Introduction . . . 1032
Genomics in MS . . . 1032
Transcriptomics in MS . . . 1034
Immunomics in MS . . . 1035
Proteomics in MS . . . 1036
Conclusion . . . 1037
References . . . 1037
86. Inflammatory Bowel Disease . . . 1040
Ad A. van Bodegraven and Cisca Wijmenga
Introduction . . . 1040
Predisposition (Genetic and Non-genetic) . . . 1041
Screening . . . 1043
Diagnosis . . . 1044
Prognosis . . . 1045
Pharmacogenomics . . . 1047
Monitoring . . . 1047
Novel and Emerging Therapeutics . . . 1048
Conclusions . . . 1049
References . . . 1050
87. Glomerular Disorders . . . 1056
Tadashi Yamamoto, Hidehiko Fujinaka and Visith
Thongboonkerd
Introduction . . . 1056
Techniques for Detection, Quantifi cation, and
Profiling of mRNA Expression in the Kidney . . . 1056
mRNA Expression Profiles of Glomerular Disorder . . 1059
Genome Variations in Glomerular Disorder . . .1060
Genetics of Congenital Glomerular Disorders . . . 1062
Genomic Medicine for Glomerular Disorders . . . 1062
Conclusions . . . 1064
References . . . 1064
88. Spondyloarthropathies . . . 1067
Dirk Elewaut, Filip De Keyser, Filip Van den Bosch,
Dieter Deforce and Herman Mielants
Introduction . . . 1067
Characteristics of SPA . . . 1067
Role of Bowel Infl ammation . . . 1070
Histopathology of Synovitis in SPA 1072
Gut and Synovium Transcriptomes . . . 1074
Proteome Analysis . . . . 1075
Novel and Emerging Therapeutics and Biomarkers . . . 1075
Conclusion . . . 1077
References . . . 1078
89. Asthma Genomics . . . 1084
Scott T. Weiss, Benjamin A. Raby and Juan C. Celedón
Introduction . . . 1084
Asthma: Basic Pathobiology . . . 1084
Predisposition (Genetic and Non-genetic) to Asthma . . . 1085
Genome-wide Linkage Analyses of Asthma and its Intermediate Phenotypes . . . 1085
Candidate-gene Association Studies of Asthma . . . 1087
Genome-wide Association Studies of Asthma . . . 1088
Asthma Genomics . . . 1088
Screening . . . 1088
Diagnosis . . . 1091
Prognosis . . . 1091
Pharmacogenetics . . . 1091
Monitoring . . . 1092
Novel and Emerging Therapeutics . . . 1093
Conclusions . . . 1093
Acknowledgements . . . 1093
References . . . 1093
Recommended Resources . . . 1097
90. Genomic Aspects of Chronic Obstructive
Pulmonary Disease . . . 1098
Peter J. Barnes
Introduction . . .1098
Predisposition . . . 1098
Pathophysiology . . . 1099
Cellular and Molecular Mechanisms . . . 1101
Diagnosis and Screening . . . 1104
Prognosis . . . 1105
Management . . . 1105
New Treatments . . . 1107
Conclusions . . .1107
References . . . 1108
91. Genomic Determinants of Interstitial Lung
Disease . . . 1110
P.W. Noble and M.P. Steele
Introduction . . . 1110
Genetic Determinants of Dpld in Mouse Strains . . . 1111
Genetic Determinants of Sarcoidosis . . . 1111
Surfactant Proteins and Dpld . . . 1114
Genetic Determinants of Pulmonary Fibrosis
Identified in Rare Inherited Disorders . . . 1115
Genetic Determinants of Fip . . . 1115
Conclusion . . . 1117
References . . . 1118
92. Peptic Ulcer Disease . . . 1122
J. Holton
Introduction . . . 1122
Clinical and Physiological Aspects of Pud . . . 1123
Pathophysiology of Ulcer Formation . . . 1124
The Helicobacter Genome . . . 1125
Human Polymorphism and Pud . . . 1130
Genomics in the Management of Disease . . . 1131
Future Developments in the use of Genomic
Techniques in Relation to Pud . . . 1132
Conclusions . . . 1132
Acknowledgements . . . 1133
References . . . 1133
Recommended Resources . . . 1137
93. Cirrhosis in the Era of Genomic Medicine . . . 1138
N.A. Shackel, K. Patel and J. McHutchison
Introduction . . . 1138
Liver Structure . . . 1138
Fibrosis and Cirrhosis . . . 1140
Diagnosis of Cirrhosis . . . 1140
Treatment of Cirrhosis . . . 1141
Genetics of Cirrhosis . . . 1142
The Liver Transcriptome . . . 1143
The Liver Proteome . . . 143
Development of Liver Fibrosis . . . 1144
Transcriptome Analysis of Liver Disease . . . 1146
Proteomic Studies of Liver Disease . . . 1148
Proteomics in Other Liver Disease . . . 1150
Future Impact of Genomics Studies . . . 1151
Conclusion . . . 1151
References . . . 1151
94. Systemic Sclerosis . . . 1155
Ulf Müller-Ladner
Introduction . . . 1155
Predisposition . . . 1155
Screening . . . 1158
Diagnosis . . . 1159
Prognosis . . . 1159
Pharmacogenomics . . . 1159
Monitoring and Genomic Factors . . . 1159
Therapeutic Strategies . . . 1162
Novel and Emerging Therapeutics . . . 1164
Conclusions . . . 1165
Acknowledgements . . . 1165
References . . . 1165
Section 11 Metabolic Disease Genomic Medicine . . . 1169
95. Genomic Medicine of Obesity . . . 1170
J. Alfredo Martínez
Introduction . . . 1170
Obesity: Causes and Genetic Predisposition . . . 1170
Search of Genes Involved in Obesity . . . 1172
Diagnosis and Characterization of Genes Associated
with Obesity . . . 1175
Screening and Diagnosis . . . 1179
Prognosis and Gene Based-treatments . . . 1180
Novel and Emerging Therapeutics Nutrigenomics,
Pharmacogenomics and Gene Therapy . . .1182
Conclusions . . . 1183
Acknowledgements . . . 1183
References . . . 1184
96. Diabetes . . . 1187
Maggie Ng and Nancy J. Cox
Introduction . . . 1187
GWAS in Type 2 Diabetes . . . 1188
Future Research in Type 2 Diabetes Genetics . . . 1190
GWAS in Type 1 Diabetes . . . 1191
Future Studies in Type 1 Diabetes . . . 1192
Clinical Utility of Genetic Research in Diabetes . . . 1192
Conclusion . . . 1192
References . . . 1192
97. Metabolic Syndrome . . . 1194
Rebecca L. Pollex and Robert A. Hegele
Introduction . . . 1194
Diagnosis: Defi nition of the MetS Phenotype . . . 1194
Pathophysiology of MetS in Brief . . . 1196
Genetics of MetS . . . 1196
Conclusion . . . 1200
Acknowledgements . . . 1200
References . . . 1200
Recommended Resources . . . 1202
98. Nutrition and Diet in the Era of Genomics . . . 1204
Jose M. Ordovas and Dolores Corella
Introduction . . . 1204
Methodological Issues . . . 1205
Gene–Nutrient Interactions . . . 1206
Path Forward . . . 1214
Conclusions . . . 1214
Acknowledgements . . . 1215
References . . . 1215
Section 12 Neuropsychiatric Disease Genomic Medicine . . . 1221
99. The Genetic Approach to Dementia . . . 1222
Robert L. Nussbaum
Introduction . . . 1222
Incidence of Dementia . . . 1223
Primary Dementias . . . 1224
Clinical Approach to the Dementias . . . 1229
Future Prospects for Genomic Medicine in the
Dementias . . . 1229
Conclusion . . . 1230
References . . . 1230
Recommended Resources . . . 1232
100. Parkinson’s Disease: Genomic Perspectives . . . 1233
Shushant Jain and Andrew B. Singleton
Introduction . . . 1233
Clinical Characteristics of PD . . . 1233
Genetics of PD . . . 1235
Genetics of Sporadic PD . . . 1238
Conclusion . . . 1241
References . . . 1241
Recommended Resources . . . 1242
101. Epilepsy Predisposition and Pharmacogenetics . . . 1243
Nicole M. Walley and David B. Goldstein
Introduction . . . 1243
Mendelian Epilepsies . . . 1243
Common Epilepsies . . . 1248
Future Program of Work . . . 1251
References . . . 1252
102. Ophthalmology . . . 1256
Janey L. Wiggs
Introduction . . . 1256
Extraocular Muscles . . . 1257
Cornea . . . 1257
Lens . . . 1259
Iris . . . 1259
Trabecular Meshwork . . . 1259
Optic Nerve . . . 1260
Retina . . . 1260
Genetic Testing for Ocular Disorders . . . 1261
Summary . . . 1261
References . . . 1261
103. Genomic Basis of Neuromuscular Disorders . . . 1265
Erynn S. Gordon and Eric P. Hoffman
Introduction . . . 1265
Motor Neuron Disease . . . 1265
Disorders of the Neuromuscular Junction . . . 1266
Disorders of the Muscle . . . 1268
Predisposition . . . 1268
Screening . . . 1273
Diagnosis . . . 1274
Prognosis . . . 1274
Monitoring . . . 1275
Current, Novel, and Emerging Therapies . . . 1276
Advances in Genomics and Proteomics . . . 1277
Conclusion . . . 1279
References . . . 1279
Recommended Resources . . . 1281
104. Psychiatric Disorders . . . 1282
Stephan Züchner and Ranga Krishnan
Introduction . . . 1282
Great Prospect, But are We There Yet? . . . 1282
Classifi cation Reconsidered . . . 1283
How Complex Can it Be? . . . 1283
The Value of Rare Genetic Variation . . . 1284
Converging Methods . . . 1284
Personalized Medicine . . . 1285
Conclusion . . . 1286
References . . . 1287
105. Genomics and Depression . . . 1289
Brigitta Bondy
Introduction . . . 1289
Diagnosis, Prevalence and Course of Depression . . . 1289
Pathophysiological Mechanisms . . . 1290
Pharmacogenomics of Antidepressants . . . 1293
Current Concepts . . . 1294
Future Aspects . . . 1296
References . . . 1296
106. Bipolar Disorder in the Era of Genomic Psychiatry . . . 1299
Ayman H. Fanous, Frank Middleton, Carlos N. Pato
and Michele T. Pato
Introduction . . . 1299
Diagnosis . . . 1299
Predisposition . . . 1300
Pharmacogenetics . . . 1304
The Role of New Technologies in Elucidating the
Genetics of BPD . . . 1305
Conclusion . . . 1308
References . . . 1308
Section 13 Infectious Disease Genomic Medicine 1313
107. Genomic Approaches to the Host
Response to Pathogens . . . 1314
M. Frances Shannon
Introduction . . . 1314
Genetic Susceptibility to Pathogens . . . 1315
Exploring the Host Response Through Expression
Profiling . . . 1317
Genetical Genomics and Systems Biology: the
New Frontiers . . . 1320
Application to Clinical Practice . . . 1320
Acknowledgement . . . 1320
References . . . 1320
Recommended Resources . . . 1323
108. Genomic Medicine and AIDS . . . 1324
Thomas Hirtzig, Yves Lévy and Jean-François Zagury
Introduction . . . 1324
Context of HIV and AIDS . . . 1324
Predisposition: Susceptibility to HIV-1 Infection . . . 1328
Diagnosis . . . 1328
Prognosis . . . 1329
Monitoring . . . 1331
Pharmacogenomics . . . 1331
Novel and Emerging Therapeutics . . . 1333
Conclusion . . . 1334
References . . . 1334
109. Viral Genomics and Antiviral Drug . . . 1340
Roberto Patarca
Introduction . . . 1340
Viral Genomics and the Antiviral Drug Revolution
Era . . . 1341
Conclusion . . . 1344
References . . . 1345
110. Host Genomics and Bacterial Infections . . . 1347
Melissa D. Johnson and Mihai Netea
Introduction . . . 1347
Genomics and the Study of Bacterial Infections . . . 1347
Host Genomics and Gram-positive, Gram-negative and Mycobacterial Infections . . . 1351
Future Directions . . . 1357
Conclusions . . . 1357
References . . . 1357
111. Sepsis and the Genomic Revolution . . . 1362
Christopher W. Woods, Robert J. Feezor and Stephen F.
Kingsmore
Introduction . . . 1362
Genetic Polymorphisms Associated with Sepsis . . . 1363
Molecular Signatures and Sepsis . . . 1368
Therapeutics . . . 1371
Conclusion . . . 1371
References . . . 1372
112. Diagnosis, Management and Disease Mechanisms
of Hepatitis in the Era of Genomic Medicine . . . 1375
N.A. Shackel, K. Patel and J. McHutchison
Introduction . . . 1375
Virology of Hepatitis Viruses . . . 1375
Acquisition and Predisposition to Viral Hepatitis . . . 1377
Screening and Diagnosis of Viral Hepatitis . . . 1378
Pathogenesis of Viral Hepatitis . . . 1380
Therapeutics and Pharmacogenomics . . . 1384
Future Impact of Genomics Studies . . . 1386
Conclusion . . . 1386
References . . . 1386
Glossary . . . 1391
Index . . . 1407