Essentials of Genomic and Personalized Medicine (eBook)

Front Cover 1
Essentials of Genomic and Personalized Medicine 4
Copyright Page 5
Table of Contents 6
Preface 10
Abbreviations 12
Contributors 20
Chapter 1 The Foundations of Genomic and Personalized Medicine 22
GENOMIC AND PERSONALIZED MEDICINE 22
GENES, GENOMES, AND DISEASE 25
FROM THE GENOME TO PERSONALIZED MEDICINE 26
CHALLENGES IN THE TRANSLATION OF GENOMICS TO HUMAN HEALTH 27
THE FUTURE OF PERSONALIZED MEDICAL CARE 28
REFERENCES 29
SECTION 1 BASICS 32
Chapter 2 Organization, Variation and Expression of the Human Genome 34
INTRODUCTION 34
THE HUMAN GENOME 35
VARIATION IN THE HUMAN GENOME 37
EXPRESSION OF THE HUMAN GENOME 40
GENOME SEQUENCING 41
REFERENCES 44
RECOMMENDED RESOURCES 47
Chapter 3 DNA Sequencing for the Detection of Human Genome Variation 48
INTRODUCTION 48
DNA SEQUENCING 49
ACKNOWLEDGEMENTS 57
REFERENCES 57
Chapter 4 Genome-Wide Association Studies and Genotyping Technologies 59
INTRODUCTION 59
PRINCIPLES OF GENOME-WIDE ASSOCIATION STUDIES 59
PLATFORM OVERVIEW 61
REFERENCES 65
Chapter 5 Copy Number Variation and Human Health 67
INTRODUCTION 67
BASIC PRINCIPLES OF CNVs 67
DETECTING CNVs IN A GENOME-WIDE MANNER 71
ASSOCIATION OF CNVs WITH DISEASE AND DISEASE SUSCEPTIBILITY 73
IMPLICATIONS OF CNVs 75
ACKNOWLEDGEMENTS 79
REFERENCES 79
RECOMMENDED RESOURCES 80
Chapter 6 DNA Methylation Analysis: Providing New Insight into Human Disease 81
INTRODUCTION 81
TECHNOLOGY TO ASSESS DNA METHYLATION 82
CLINICAL IMPACT OF DNA METHYLATION ANALYSIS 86
REFERENCES 90
RECOMMENDED RESOURCES 93
Chapter 7 DNA Microarrays in Biological Discovery and Patient Care 94
INTRODUCTION 94
MICROARRAY TECHNOLOGY 94
DATA ANALYSIS 97
APPLICATIONS 98
LIMITATIONS AND CHALLENGES 101
FUTURE DIRECTIONS 102
REFERENCES 105
RECOMMENDED RESOURCES 109
Chapter 8 Proteomics: The Deciphering of the Functional Genome 110
INTRODUCTION 110
GEL-BASED AND SOLUTION-BASED PROTEOMICS 111
MASS SPECTROMETRY 112
BIOINFORMATICS 113
IMPACT OF PROTEOMICS ON UNDERSTANDING DISEASES 115
ACKNOWLEDGEMENTS 117
REFERENCES 117
RECOMMENDED RESOURCES 117
Chapter 9 Comprehensive Metabolic Analysis for Understanding of Disease 118
INTRODUCTION 118
CURRENT METABOLOMICS PLATFORMS: BASIC TOOLS AND GENERAL FEATURES 119
COMPARISON OF NMR AND MS TECHNOLOGIES FOR UNBIASED METABOLIC PROFILING 120
MS METHODS FOR TARGETED METABOLIC PROFILING 121
EXAMPLES OF NMR-BASED METABOLIC PROFILING IN DISEASE RESEARCH 122
EXAMPLES OF TARGETED MS-BASED METABOLIC PROFILING FOR UNDERSTANDING OF DISEASE MECHANISMS 122
REFERENCES 126
SECTION 2 INFORMATICS 130
Chapter 10 Bioinformatic and Computational Analysis for Genomic Medicine 132
INTRODUCTION 132
VIGNETTES: HOW SPECIFIC BIOINFORMATICS METHODS CAN CHANGE THE PRACTICE OF MEDICINE 133
ANALYTIC METHODS 139
WHERE DATA FOR STUDIES MAY BE FOUND 140
BIOINFORMATICS VOCABULARIES AND ONTOLOGIES 141
FREELY AVAILABLE BIOINFORMATICS TOOLS 142
ACKNOWLEDGEMENTS 147
REFERENCES 147
RECOMMENDED RESOURCES 151
Chapter 11 Systems Biology and Systems Medicine 152
INTRODUCTION 152
SYSTEMS SCIENCE IN BIOLOGY AND MEDICINE 153
MULTI-PARAMETER BLOOD-BOURNE BIOMARKERS 154
EMERGING IN VIVO AND IN VITRO TECHNOLOGIES 155
COMPUTATIONAL AND MATHEMATICAL CHALLENGES IN SYSTEMS MEDICINE 158
REFERENCES 160
RECOMMENDED RESOURCES 162
Chapter 12 Electronic Medical Records in Genomic Medicine Practice and Research 163
INTRODUCTION 163
EMRs AND GENOMIC MEDICINE CLINICAL PRACTICE 164
EMRs AND GENOMIC MEDICINE RESEARCH 166
ACKNOWLEDGEMENTS 170
REFERENCES 170
RECOMMENDED RESOURCES 171
Chapter 13 Online Health Information Retrieval by Consumers 172
INTRODUCTION 172
CHARACTERISTICS OF CONSUMER SEARCHES FOR HEALTH INFORMATION 172
WHAT AND WHERE ARE CONSUMERS SEARCHING? 173
PERSONALIZED GENOMICS FOR CONSUMERS 175
REFERENCES 179
WIKIPEDIA REFERENCES 180
SECTION 3 TRANSLATIONAL 182
Chapter 14 Translational Genomics: From Discovery to Clinical Practice 184
INTRODUCTION 184
A ROADMAP FOR TRANSLATION 185
WHERE CAN GENOMICS HAVE IMPACT IN THE CONTINUUM OF HEALTH AND DISEASE? 185
TRANSLATIONAL GENOMICS: ENABLING COMPETENCIES 186
DEVELOPING ENVIRONMENTS THAT FOSTER TRANSLATIONAL GENOMICS TO HEALTH APPLICATIONS 190
REFERENCES 194
Chapter 15 Pharmacogenetics and Pharmacogenomics 196
INTRODUCTION 196
PHARMACOGENETIC STUDIES: FROM CONCEPT TO PRACTICE 198
MARKER SELECTION – STRATEGY AND APPLICATION 200
FROM BENCH TO BEDSIDE: INTEGRATION OF PHARMACOGENETIC TESTING INTO CLINICAL PRACTICE 203
EXAMPLES OF PGx TESTS: PROMISING NEW DEVELOPMENTS AND MARKETED PRODUCTS 204
FUTURE DEVELOPMENTS REQUIRED FOR THE FIELD TO FULLY MEET ITS EXPECTATIONS 206
REFERENCES 209
RECOMMENDED RESOURCES 211
Chapter 16 Clinical Implementation of Translational Genomics 212
INTRODUCTION 212
GENETIC STRATIFICATION WILL ALLOW MEDICAL CARE TO BE INDIVIDUALIZED AFTER A DIAGNOSIS IS MADE 212
POPULATION-BASED GERMLINE GENOMIC SCREENING 213
NEWBORN SCREENING 214
SOMATIC GENOMIC VARIATION 215
NOVEL SOURCES OF GENOMIC VARIATION 215
LABORATORY STANDARDS TO ENSURE ANALYTIC VALIDITY 215
CLINICAL VALIDATION AND CLINICAL UTILITY 216
COST 217
REIMBURSEMENT 217
WHO WILL PROVIDE GENOMIC MEDICAL CARE? 217
GENOMIC LITERACY 218
ACKNOWLEDGEMENTS 220
REFERENCES 220
RECOMMENDED RESOURCES 221
Chapter 17 The Role of Genomics in Enabling Prospective Health Care 222
INTRODUCTION 222
PREDICTIVE MODELS 224
PREDICTIVE FACTORS 224
ACKNOWLEDGEMENTS 228
REFERENCES 228
RECOMMENDED RESOURCES 229
Chapter 18 Genome Policy Considerations for Genomic Medicine 230
INTRODUCTION 230
GENOME RESEARCH AFTER THE HUMAN GENOME PROJECT 231
POLICY ISSUES IN LARGE-SCALE GENETICS AND GENOMICS RESEARCH 232
INTEGRATING GENOMIC MEDICINE APPLICATIONS IN HEALTHCARE 234
REFERENCES 239
Chapter 19 Federal Regulation of Genomic Medicine 244
INTRODUCTION 244
REGULATION OF GENOMIC TESTS 246
PHARMACOGENOMICS IN DRUG DEVELOPMENT AND CLINICAL MEDICINE: THE ROLE OF REGULATION 248
REFERENCES 252
RECOMMENDED RESOURCES 253
Chapter 20 Economic Issues and Genomic Medicine 254
INTRODUCTION 254
ECONOMIC EVALUATION AND COST-EFFECTIVENESS ANALYSIS 254
EVALUATING GENOMIC TECHNOLOGIES 256
ECONOMIC INCENTIVES AND THE FUTURE OF GENOMIC MEDICINE 258
ESTABLISHING VALUE-BASED REIMBURSEMENT FOR GENOMIC TECHNOLOGIES 260
ECONOMIC CHALLENGES 261
REFERENCES 264
Chapter 21 Public Health Genomics 266
INTRODUCTION 266
THE DEFINITION OF PUBLIC HEALTH GENOMICS 266
KEY CONCEPTS IN PUBLIC HEALTH GENOMICS 267
THE “ENTERPRISE” OF PUBLIC HEALTH GENOMICS 268
CORE ACTIVITIES IN PUBLIC HEALTH GENOMICS 269
THE ROLE OF PUBLIC HEALTH IN THE TRANSLATION OF HUMAN GENOME DISCOVERIES INTO HEALTH APPLICATIONS 271
THE FOCUS ON DISEASE PREVENTION AND HEALTH PROMOTION 271
REFERENCES 274
RECOMMENDED RESOURCES 276
SECTION 4 CLINICAL (CARDIOLOGY) 278
Chapter 22 The Genomics of Hypertension 280
INTRODUCTION 280
PREDISPOSITION 281
DIAGNOSIS 283
PROGNOSIS 284
PHARMACOGENOMICS 285
ACKNOWLEDGEMENTS 288
REFERENCES 288
RECOMMENDED RESOURCES 289
Chapter 23 Lipoprotein Disorders 290
INTRODUCTION 290
OVERVIEW OF LIPOPROTEIN METABOLISM 290
PLASMA LIPID AND LIPOPROTEIN LEVELS AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE 292
INHERITED BASIS FOR BLOOD LIPID TRAITS 292
SCREENING FOR LIPID DISORDERS 293
GENETICS OF LDL-C 293
GENETICS OF HDL-C 295
GENETICS OF TRIGLYCERIDES 298
GENETIC LIPID DISORDERS WITHOUT CURRENT PROVEN MOLECULAR ETIOLOGY 299
INFLUENCE OF LIPID-MODULATING MUTATIONS ON RISK OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE 299
FUTURE DIRECTIONS IN GENETICS AND GENOMICS OF LIPOPROTEINS 300
PHARMACOGENETICS OF LIPID-MODULATING THERAPIES 302
IMPLICATIONS OF GENOMICS OF LIPOPROTEIN METABOLISM FOR THE DEVELOPMENT OF NOVEL THERAPIES 302
CLINICAL RECOMMENDATIONS FOR GENETIC TESTING FOR LIPID DISORDERS 303
ACKNOWLEDGEMENTS 306
REFERENCES 306
RECOMMENDED RESOURCES 309
Chapter 24 Genomics of Myocardial Infarction 310
INTRODUCTION 310
PREDISPOSITION 310
SCREENING STRATEGIES 316
PROGNOSTIC IMPLICATIONS OF MI 317
PHARMACOGENOMICS OF MI 317
NOVEL AND EMERGING THERAPIES 318
REFERENCES 320
RECOMMENDED RESOURCES 323
Chapter 25 Acute Coronary Syndromes 324
INTRODUCTION 324
PREDISPOSITION 324
SCREENING 325
DIAGNOSIS 326
PROGNOSIS 329
ACKNOWLEDGEMENTS 331
REFERENCES 331
RECOMMENDED RESOURCES 333
Chapter 26 Heart Failure in the Era of Genomic Medicine 334
INTRODUCTION 334
PREDISPOSITION (GENETIC AND NON-GENETIC) 334
SCREENING 335
PATHOPHYSIOLOGY 336
DIAGNOSIS 337
PROGNOSIS 338
PHARMACOGENOMICS 339
MONITORING 340
ACKNOWLEDGEMENTS 344
REFERENCES 344
Chapter 27 Genomic Assessment of Cardiac Transplant Rejection 347
INTRODUCTION 347
CARDIAC ALLOTRANSPLANTATION AS A DEFINITIVE THERAPY FOR END-STAGE HEART FAILURE 347
THE PROBLEM OF ALLOGRAFT REJECTION 348
IMMUNOSUPPRESSION STRATEGIES TO PREVENT REJECTION 348
CURRENT STRATEGIES FOR MONITORING TRANSPLANT REJECTION 349
THE CARGO CLINICAL STUDY 351
DEVELOPMENT OF A GENE EXPRESSION SIGNATURE FOR CARDIAC TRANSPLANT REJECTION 351
PATHWAYS MONITORED BY THE GEP (AlloMap™) TEST 352
VARIABILITY OF THE BIOPSY GOLD STANDARD AND RELATIONSHIP TO THE GEP (AlloMap™) SCORE 352
DISCORDANCE BETWEEN BIOPSY GRADE AND MOLECULAR SCORE 352
EFFECT OF TIME POST-TRANSPLANTATION ON PERFORMANCE OF THE GEP TEST 353
RELATIONSHIP OF GEP SCORE TO CORTICOSTEROID DOSE 353
PREDICTION OF FUTURE ACR BY MOLECULAR SCORE 353
CLINICAL USE OF THE AlloMap™ TEST 354
REFERENCES 355
Chapter 28 Genetics and Genomics of Hypertrophic Cardiomyopathy 357
INTRODUCTION 357
DEFINITIONS, CLINICAL PRESENTATION, AND DIAGNOSIS 357
MOLECULAR GENETICS OF HCM 359
SCREENING AND TREATMENT FOR HCM 363
REFERENCES 367
Chapter 29 Genetics and Genomics of Arrhythmias 371
INTRODUCTION 371
SPECIFIC CARDIAC ARRHYTHMIAS 371
PRIMARY ABNORMALITIES IN CARDIAC RHYTHM: VENTRICULAR TACHYARRHYTHMIAS 371
COMPLEX FORMS OF LQTS 378
SHORT QT INTERVAL SYNDROME 382
FAMILIAL VT/CPVT 382
PRIMARY CONDUCTION ABNORMALITIES 383
REFERENCES 387
Chapter 30 Genetics and Genomics in the Management of Hemostasis and Thrombosis 395
INTRODUCTION 395
GENETICS OF COAGULATION 395
HUMAN HEMOSTATIC VARIABILITY 397
GENOTYPE–PHENOTYPE INFLUENCES 397
GENE-ENVIRONMENT INFLUENCES ON HEMOSTASIS 398
CIRCULATING CELLULAR AND PROTEIN INFLUENCES ON HEMOSTASIS AND THROMBOSIS 399
LINKAGE STUDIES IN THROMBOSIS 400
ASSOCIATION STUDIES IN THROMBOSIS 401
HERITABILITY AND THROMBOSIS: EXISTING COMPLEXITIES 401
A PERSONALIZED APPROACH TO HEMOSTASIS AND THROMBOSIS 401
PATIENT SCREENING: A TRADITIONAL PARADIGM 401
PATIENT SCREENING: A COMPREHENSIVE AND POPULATION-BASED APPROACH 402
PROGNOSTIC CONSIDERATIONS 403
EMERGING PLATFORM FOR HEMOSTASIS AND THROMBOSIS RESEARCH 405
REFERENCES 409
Chapter 31 Genomics of Congenital Heart Disease 411
INTRODUCTION 411
CHD GENE DISCOVERY BY CONVENTIONAL GENETICS 411
GENOMIC STRATEGIES FOR CHD GENE DISCOVERY 416
CYTOGENETIC AND MOLECULAR GENETIC TESTING 417
MEDICAL EVALUATION AND COUNSELING RECOMMENDATIONS 418
ACKNOWLEDGEMENTS 421
REFERENCES 421
RECOMMENDED RESOURCES 423
SECTION 5 CLINICAL (ONCOLOGY) 426
Chapter 32 Genomics in the Management of Lymphomas 428
INTRODUCTION 428
DIFFUSE LARGE B-CELL LYMPHOMA 431
PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA 432
HODGKIN LYMPHOMA 433
FOLLICULAR LYMPHOMA 434
MANTLE CELL LYMPHOMA 436
BURKITT LYMPHOMA 436
REFERENCES 438
Chapter 33 Genomics in Leukemias 442
INTRODUCTION 442
GENOMICS IN LEUKEMIAS: INSIGHTS INTO LEUKEMIA BIOLOGY 444
GENOMICS IN LEUKEMIAS: EVALUATION OF DRUG EFFECTS 445
GENOMICS IN LEUKEMIAS: CLINICAL OUTCOME PREDICTION 447
ACKNOWLEDGMENTS 450
REFERENCES 450
RECOMMENDED RESOURCES 452
Chapter 34 Genomics in the Diagnosis and Management of Lung Cancer 453
INTRODUCTION 453
EARLY DIAGNOSIS/SCREENING OF LUNG CANCER 454
CLASSIFICATION AND PROGNOSIS 456
PATHOGENESIS AND TREATMENT OF LUNG CANCER 459
REFERENCES 464
RECOMMENDED RESOURCE 466
Chapter 35 Genomics in the Diagnosis and Management of Breast Cancer 467
INTRODUCTION 467
THE PROMISE 467
GENETIC BASES 469
MOLECULAR BASES 469
PROGNOSIS AND PREDICTION 470
MOLECULAR MARKERS 470
GENOMIC INSIGHTS 471
NETHERLANDS CANCER INSTITUTE STUDY 471
DUKE-TAIPEI STUDY 473
NSABP STUDY 473
PATHWAY PREDICTION 474
THE REALITY OF CLINICAL GENOMICS 474
REFERENCES 476
Chapter 36 Colorectal Cancer 478
INTRODUCTION 478
GENOMIC MODEL OF CRC 479
PREDISPOSITION FOR CRC 481
RISK ASSESSMENT, EVALUATION, AND GENETIC TESTING 486
SCREENING AND SURVEILLANCE 488
PROGNOSIS AND TREATMENT 488
PHARMACOGENETICS/GENOMICS OF CHEMOPREVENTION AND CHEMOTHERAPY 489
REFERENCES 492
Chapter 37 Genomic Evaluation and Management of Prostate Cancer 498
INTRODUCTION 498
GENETIC PREDISPOSITION AND ALTERATIONS IN PROSTATE CANCER 498
PROSTATE CANCER DETECTION 501
GENOMIC CHANGES ASSOCIATED WITH PROSTATE CANCER BEHAVIOR 504
GENOMIC CHANGES ASSOCIATED WITH HORMONE-REFRACTORY PROSTATE CANCER 506
REFERENCES 509
Chapter 38 Genomic Assessment of Ovarian Cancer 514
INTRODUCTION 514
INHERITED OVARIAN CANCER SYNDROMES 514
OPTIONS FOR SCREENING AND PREVENTION 515
GENOMIC INSTABILITY AND OVARIAN CANCER 515
SOMATIC MUTATIONS IN OVARIAN CANCER 515
ONCOGENES AND GROWTH FACTORS 516
TUMOR SUPPRESSOR GENES 517
EPIGENETICS IN OVARIAN CARCINOGENESIS 517
OVARIAN CANCER METASTASES 517
REFERENCES 520
Chapter 39 Genomic Evaluation of Pancreatic Neoplasms 522
INTRODUCTION 522
PREDISPOSITION (GENETIC AND NON-GENETIC) 523
SCREENING 523
DIAGNOSIS 524
PROGNOSIS 526
REFERENCES 529
Chapter 40 Genomic Evaluation of Head and Neck Cancer 532
INTRODUCTION 532
HEAD AND NECK SQUAMOUS CELL CARCINOMA 532
GENOMICS OF HNSCC: CLINICAL APPLICATIONS 538
REFERENCES 540
RECOMMENDED RESOURCES 542
Chapter 41 Genomic Evaluation of Brain Tumors and Gliomas 543
INTRODUCTION 543
PREDISPOSITION 544
DIAGNOSIS AND PROGNOSIS 545
PHARMACOGENOMICS 548
SUMMARY 548
REFERENCES 550
Chapter 42 Targeted Therapies for Cancer 553
INTRODUCTION 553
TARGETED THERAPIES FOR CANCER 553
THE IDEAL TARGET 553
THE FIRST DIAGNOSTIC-THERAPEUTIC COMBINATION IN CANCER THERAPY: HORMONAL THERAPY FOR BREAST CANCER 554
DIAGNOSTIC-THERAPEUTIC COMBINATIONS FOR LEUKEMIA AND LYMPHOMA 554
HER-2 POSITIVE BREAST CANCER AND TRASTUZUMAB (HERCEPTIN®) 555
OTHER TARGETED ANTICANCER THERAPIES USING ANTIBODIES 556
SELECTED TARGETED ANTICANCER THERAPIES USING SMALL MOLECULES 561
REFERENCES 565
SECTION 6 CLINICAL (INFLAMMATORY DISEASE) 570
Chapter 43 Genomics in the Evaluation and Management of Rheumatoid Arthritis 572
INTRODUCTION 572
PREDISPOSITION 573
SCREENING 578
DIAGNOSIS, PROGNOSIS, AND MONITORING 579
REFERENCES 582
Chapter 44 Genomic Evaluation of Multiple Sclerosis 587
INTRODUCTION 587
GENOMICS IN MS 587
TRANSCRIPTOMICS IN MS 589
IMMUNOMICS IN MS 590
PROTEOMICS IN MS 591
REFERENCES 593
Chapter 45 Genomic Assessment of Inflammatory Bowel Disease 596
INTRODUCTION 596
PREDISPOSITION (GENETIC AND NON-GENETIC) 597
SCREENING 599
DIAGNOSIS 600
PROGNOSIS 601
PHARMACOGENOMICS 603
REFERENCES 606
Chapter 46 Asthma Genomics 611
INTRODUCTION 611
ASTHMA: BASIC PATHOBIOLOGY 611
PREDISPOSITION (GENETIC AND NON-GENETIC) TO ASTHMA 612
GENOME-WIDE LINKAGE ANALYSES OF ASTHMA AND ITS INTERMEDIATE PHENOTYPES 612
CANDIDATE-GENE ASSOCIATION STUDIES OF ASTHMA 614
GENOME-WIDE ASSOCIATION STUDIES OF ASTHMA 615
ASTHMA GENOMICS 615
PHARMACOGENETICS 615
ACKNOWLEDGEMENTS 619
REFERENCES 619
RECOMMENDED RESOURCE 623
Chapter 47 Genomics in the Evaluation and Management of Chronic Obstructive Pulmonary Disease 624
INTRODUCTION 624
PREDISPOSITION 624
PATHOPHYSIOLOGY 625
CELLULAR AND MOLECULAR MECHANISMS 627
DIAGNOSIS AND SCREENING 630
PROGNOSIS 631
MANAGEMENT 631
REFERENCES 635
Chapter 48 Genetics and Genomics of Interstitial Lung Disease 637
INTRODUCTION 637
GENETIC DETERMINANTS OF SARCOIDOSIS 638
SURFACTANT PROTEINS AND DPLD 640
GENETIC DETERMINANTS OF PULMONARY FIBROSIS IDENTIFIED IN RARE INHERITED DISORDERS 641
GENETIC DETERMINANTS OF FIP 641
REFERENCES 645
Chapter 49 Peptic Ulcer Disease 648
INTRODUCTION 648
PATHOPHYSIOLOGY OF ULCER FORMATION 649
THE HELICOBACTER GENOME 650
HUMAN POLYMORPHISM AND PUD 656
GENOMICS IN THE MANAGEMENT OF DISEASE 656
ACKNOWLEDGEMENTS 659
REFERENCES 659
RECOMMENDED RESOURCES 663
SECTION 7 CLINICAL (METABOLIC DISEASE) 664
Chapter 50 Genomics in Pathogenesis of Cirrhosis 666
INTRODUCTION 666
FIBROSIS AND CIRRHOSIS 666
DIAGNOSIS OF CIRRHOSIS 667
GENETICS OF CIRRHOSIS 667
THE LIVER TRANSCRIPTOME 669
THE LIVER PROTEOME 670
DEVELOPMENT OF LIVER FIBROSIS 670
TRANSCRIPTOME ANALYSIS OF LIVER DISEASE 672
PROTEOMIC STUDIES OF LIVER DISEASE 674
PROTEOMICS IN OTHER LIVER DISEASE 676
REFERENCES 678
Chapter 51 Genomic Medicine and Obesity 682
INTRODUCTION 682
OBESITY: CAUSES AND GENETIC PREDISPOSITION 682
SEARCH FOR GENES INVOLVED IN OBESITY 684
DIAGNOSIS AND CHARACTERIZATION OF GENES ASSOCIATED WITH OBESITY 685
SCREENING AND DIAGNOSIS 689
PROGNOSIS AND GENE-BASED TREATMENTS 690
ACKNOWLEDGEMENTS 694
REFERENCES 694
Chapter 52 Diabetes 697
INTRODUCTION 697
GWAS IN TYPE 2 DIABETES 698
FUTURE RESEARCH IN TYPE 2 DIABETES GENETICS 700
GWAS IN TYPE 1 DIABETES 701
FUTURE STUDIES IN TYPE 1 DIABETES 702
CLINICAL UTILITY OF GENETIC RESEARCH IN DIABETES 702
REFERENCES 703
SECTION 8 CLINICAL (NEUROLOGICAL DISEASE) 706
Chapter 53 Genetics and Genomics of Dementia 708
INTRODUCTION 708
INCIDENCE OF DEMENTIA 709
PRIMARY DEMENTIAS 710
CLINICAL APPROACH TO THE DEMENTIAS 715
REFERENCES 717
RECOMMENDED RESOURCES 720
Chapter 54 Genetics and Genomics of Parkinson's Disease 721
INTRODUCTION 721
CLINICAL CHARACTERISTICS OF PD 721
GENETICS OF PD 723
GENETICS OF SPORADIC PD 726
REFERENCES 730
RECOMMENDED RESOURCES 732
Chapter 55 Genomic Considerations in Ophthalmology 733
INTRODUCTION 733
LENS 736
IRIS 736
TRABECULAR MESHWORK 736
OPTIC NERVE 737
RETINA 737
GENETIC TESTING FOR OCULAR DISORDERS 738
REFERENCES 740
Chapter 56 Genomics in the Diagnosis and Management of Depression 743
INTRODUCTION 743
DIAGNOSIS, PREVALENCE AND COURSE OF DEPRESSION 743
PATHOPHYSIOLOGICAL MECHANISMS 744
PHARMACOGENOMICS OF ANTIDEPRESSANTS 747
GENE AND PROTEIN EXPRESSION STUDIES 748
FUTURE CONSIDERATIONS 748
REFERENCES 750
SECTION 9 CLINICAL (INFECTIOUS DISEASE) 752
Chapter 57 Genomic Approaches to the Host Response to Pathogens 754
INTRODUCTION 754
GENETIC SUSCEPTIBILITY TO PATHOGENS 755
EXPLORING THE HOST RESPONSE THROUGH EXPRESSION PROFILING 757
ACKNOWLEDGEMENT 761
REFERENCES 761
RECOMMENDED RESOURCES 764
Chapter 58 Host Genomics and Bacterial Infections 765
INTRODUCTION 765
GENOMICS AND THE STUDY OF BACTERIAL INFECTIONS 765
HOST GENOMICS AND GRAM-POSITIVE, GRAM-NEGATIVE AND MYCOBACTERIAL INFECTIONS 769
REFERENCES 776
Chapter 59 Genomics in the Evaluation and Management of Sepsis 781
INTRODUCTION 781
GENETIC POLYMORPHISMS ASSOCIATED WITH SEPSIS 782
MOLECULAR SIGNATURES AND SEPSIS 787
REFERENCES 791
Chapter 60 Genomics and the Management of Hepatitis 795
INTRODUCTION 795
VIROLOGY OF HEPATITIS VIRUSES 795
ACQUISITION AND PREDISPOSITION TO VIRAL HEPATITIS 797
SCREENING AND DIAGNOSIS OF VIRAL HEPATITIS 798
PATHOGENESIS OF VIRAL HEPATITIS 799
THERAPEUTICS AND PHARMACOGENOMICS 802
REFERENCES 804
Index 808
A 808
B 812
C 813
D 819
E 821
F 822
G 824
H 826
I 829
J 831
K 831
L 831
M 834
N 837
O 838
P 839
Q 843
R 843
S 845
T 847
U 849
V 850
W 850
X 851
Y 851
Z 851