Textbook of Personalized Medicine

443 Pages·2009·9.86 MB·English

BookID 187268_ChapID FM_Proof# 1 - 24/08/2009
T extbook of Personalized Medicine
BookID 187268_ChapID FM_Proof# 1 - 24/08/2009
Kewal K. Jain
Textbook of Personalized
Medicine
BookID 187268_ChapID FM_Proof# 1 - 24/08/2009 BookID 187268_ChapID FM_Proof# 1 - 24/08/2009
Kewal K. Jain
Jain PharmaBiotech
Blaesiring 7
4057 Basel
Switzerland
BookID 187268_ChapID FM_Proof# 1 - 24/08/2009
Dedicated to Barack Obama,
President of United States who introduced
the bill titled “Genomics and Personalized
Medicine Act of 2006” in the US
Senate in 2006
BookID 187268_ChapID FM_Proof# 1 - 24/08/2009
Preface
Personalized medicine, which simply means selection of treatment best suited for
an individual, involves integration and translation of several new technologies in
clinical care of patients. The scope is much broader than indicated by the term
genomic medicine, because many non-genomic factors are taken into consideration
in developing personalized medicine. Basic technologies for personalized medi-
cine, of which molecular diagnostics has the biggest share, are mentioned briefly
and appropriate references are given for further information. Commercial aspects
are discussed briefly in a chapter and detailed analysis of markets and companies
involved in personalized medicine is presented in a special report on this topic.
There is increasing interest in personalized medicine. Considerable advances
have taken place in molecular biology and biotechnology to make personalized
medicine a viable option, but some misconceptions still exist, both in the academic
and in the commercial sectors. There is lack of a suitable source of information that
provides both the fundamentals as well as applications of personalized medicine.
As the latest version of the first monograph on personalized medicine published in
1998, this volume, Textbook of Personalized Medicine, summarizes the author’s
efforts during the past decade as well as reviews selected studies done during this
period in a readable format for the physicians and scientists. It is hoped that physi-
cians, pharmacists, scientists, and interested lay readers with basic scientific knowl-
edge will find this book useful.
Basel, Switzerland K.K. Jain MD
vii
BookID 187268_ChapID FM_Proof# 1 - 24/08/2009
Contents
Preface .............................................................................................................. vii
1 Basics of Personalized Medicine .............................................................. 1
Defnition of Personalized Medicine .......................................................... 1
History of Medical Concepts Relevant to Personalized Medicine.............. 3
Molecular Biological Basis of Personalized Medicine ............................... 5
The Human Genome ............................................................................... 6
Chromosomes ......................................................................................... 6
Genes ....................................................................................................... 7
The Genetic Code ............................................................................... 7
Gene Expression ................................................................................. 8
DNA Sequences and Structure ............................................................ 8
Single Nucleotide Polymorphisms ...................................................... 9
Genotype and Haplotypes ................................................................... 9
Genetic Variations in the Human Genome .............................................. 9
Insertions and Deletions in the Human Genome ................................ 10
Large Scale Variation in Human Genome........................................... 11
Variation in Copy Number in the Human Genome ............................. 11
Structural Variants in the Human Genome ......................................... 12
Mapping and Sequencing of Structural Variants from
Human Genomes ............................................................................. 13
1,000 Genomes Project ....................................................................... 14
Human Variome Project ...................................................................... 15
Basics Technologies for Developing Personalized Medicine ..................... 15
Definitions of Technologies Relevant to Personalized Medicine ........... 15
Problems with the ICH Definitions of Pharmacogenomics
and Pharmacogenetics ......................................................................... 16
Relationship of Various Technologies to Personalized Medicine ........... 16
Conventional Medicine vs. Personalized Medicine .................................... 17
Genetic Basis of Personalized Medicine ..................................................... 18
Genetic Medicine .................................................................................... 18
Human Disease and Genes ...................................................................... 18
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x Contents
Genetic and Environmental Interactions in Etiology
of Human Diseases ............................................................................. 19
Mass Analysis of DNA from Whole Populations ................................... 19
Role of Genetics in Development of Personalized Medicines ................ 20
Genetic Databases ............................................................................... 20
Genetic Epidemiology ........................................................................ 21
Limitations of Medical Genetics and Future Prospects ...................... 22
Genetics vs. Epigenetics ..................................................................... 22
Role of Systems Biology in Personalized Medicine ................................... 22
Systems Pharmacology ........................................................................... 24
Systems Medicine ................................................................................... 24
A Personalized Approach to Environmental Factors in Disease ................ 25
Reclassifcation of Diseases ........................................................................ 26
Summary ..................................................................................................... 27
2 Molecular Diagnostics as Basis of Personalized Medicine .................... 29
Introduction ................................................................................................. 29
Molecular Diagnostic Technologies ........................................................... 29
DNA Sequencing ........................................................................................ 30
Biochips and Microarrays ........................................................................... 30
DNA Biochip Technology for Developing Personalized Medicine ........ 30
Role of Protein Biochips in Personalized Medicine ............................... 34
Cytogenetics ................................................................................................ 35
Molecular Cytogenetics as Basis for Personalized Medicine ................. 35
Cytomics as a Basis for Personalized Medicine ..................................... 36
SNP Genotyping ......................................................................................... 37
Technologies for SNP Analysis .............................................................. 37
Applications of SNPs Relevant to Personalized Medicine ..................... 37
Concluding Remarks on SNP Genotyping ............................................. 39
Haplotyping. ................................................................................................ 40
HapMap Project ...................................................................................... 41
Predicting Drug Response with HapMap ............................................... 42
Nanodiagnostics for Personalized Medicine ............................................... 42
Cantilevers for Personalized Medical Diagnostics ................................. 43
Nanopore-Based Technology for Single Molecule Identification .......... 44
Application of Proteomics in Molecular Diagnosis .................................... 44
Comparison of Proteomic and Genomic Approaches in
Personalized Medicine ........................................................................ 44
Gene Expression Profling .......................................................................... 45
DNA Microarrays for Gene Expression Studies ..................................... 46
Analysis of Single-Cell Gene Expression ............................................... 47
Gene Expression Profiling Based on Alternative RNA Splicing ............ 47
Molecular Imaging and Personalized Medicine ......................................... 48
Monitoring In Vivo Gene Expression by Molecular Imaging ................ 49
Glycomics-Based Diagnostics .................................................................... 49
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Contents xi
Combination of Diagnostics and Therapeutics ........................................... 50
Point-of-Care Diagnosis .............................................................................. 50
Point-of-Care Diagnosis of Infections .................................................... 52
Advantages vs. Disadvantages of Point-of-Care Diagnosis .................... 52
Future Prospects of Point-of-Care Diagnosis ......................................... 53
Genetic Testing for Disease Predisposition ................................................ 53
Personal Genetic Service ........................................................................ 54
Role of Diagnostics in Integrated Healthcare ............................................. 54
Concept of Integrated Healthcare ........................................................... 54
Components of Integrated Healthcare..................................................... 55
Screening ............................................................................................. 55
Disease Prediction ............................................................................... 55
Early Diagnosis ................................................................................... 55
Prevention ........................................................................................... 56
Therapy Based on Molecular Diagnosis ............................................. 56
Monitoring of Therapy ........................................................................ 56
Advantages and Limitations of Integrated Healthcare ............................ 56
Future of Molecular Diagnostics in Personalized Medicine ....................... 57
Summary ..................................................................................................... 57
3 Role of Biomarkers in Personalized Medicine ....................................... 59
Introduction ................................................................................................. 59
Technologies for Discovery of Biomarkers ................................................ 60
Systems Biology Approach to Biomarker Identification ........................ 60
Epigenomic Technologies ....................................................................... 60
Discovery of Methylation Biomarkers ................................................ 62
Proteomic Strategies for Biomarker Identification ................................. 62
Proteomic Technologies for Detection of Biomarkers
in Body Fluids ................................................................................. 63
Biomarkers for Diagnostics ........................................................................ 63
Biomarkers for Drug Development ............................................................. 64
Use of Biomarkers for Developing MAb Therapy in Oncology ............. 64
Biobanking, Biomarkers and Personalized Medicine ................................. 65
Expression Signatures as Diagnostic/Prognostic Tools .............................. 66
Biomarkers for Monitoring Response to Therapy ...................................... 66
Drug Rescue by Biomarker-Based Personalized Medicine ........................ 67
Future Role of Biomarkers in Personalized Medicine ................................ 68
Summary ..................................................................................................... 68
4 Pharmacogenetics ..................................................................................... 69
Basics of Pharmacogenetics ........................................................................ 69
Role of Molecular Diagnostics in Pharmacogenetics ................................. 70
Role of Pharmacogenetics in Pharmaceutical Industry .............................. 71
Study of the Drug Metabolism and Pharmacological Effects ................. 71
Causes of Variations in Drug Metabolism .............................................. 72
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Enzymes Relevant to Drug Metabolism ................................................. 72
Pharmacogenetics of Phase I Metabolism .............................................. 73
Cyp450 ................................................................................................ 73
P450 CYP 2D6 Inhibition by Selective Serotonin Reuptake
Inhibitors (SSRIs) ........................................................................... 75
Cytochrome P450 Polymorphisms and Response to Clopidogrel ...... 76
Lansoprazole and Cytochrome P450 .................................................. 76
Glucose-6-Phosphate Dehydrogenase ................................................ 77
Pharmacogenetics of Phase II Metabolism ............................................. 78
N-Acetyltransferase ............................................................................ 78
Uridine Diphosphate-Glucuronosyltransferase ................................... 79
Measurement of CYP Isoforms .............................................................. 79
Polymorphism of Drug Transporters ...................................................... 80
Genetic Variation in Drug Targets........................................................... 81
Polymorphisms of Kinase Genes ........................................................ 82
Effect of Genetic Polymorphisms on Response of Disease to Drugs ..... 82
Ethnic Differences in Drug Metabolism ................................................. 83
Gender Differences in Pharmacogenetics ............................................... 83
Role of Pharmacogenetics in Drug Safety .............................................. 84
Adverse Drug Reactions ..................................................................... 84
ADRs in Children ............................................................................... 84
Genetically Determined ADRs ........................................................... 85
ADRs of Chemotherapy ...................................................................... 86
Malignant Hyperthermia ..................................................................... 87
Pharmacogenetics of Clozapine-Induced Agranulocytosis................. 87
Role of Pharmacogenetics in Warfarin Therapy ................................. 88
Role of Pharmacogenetics in Carbamazepine Therapy ...................... 89
Role of Pharmacogenetics in Statin Therapy ...................................... 89
FDA Consortium for Genetic Biomarkers of Serious
Adverse Events ............................................................................... 90
Therapeutic Drug Monitoring, Phenotyping, and Genotyping ............... 91
Therapeutic Drug Monitoring ............................................................. 91
Phenotyping ........................................................................................ 91
Genotyping .......................................................................................... 93
Genotyping vs. Phenotyping ............................................................... 93
Phenomics ............................................................................................... 94
Limitations of Genotype-Phenotype Association Studies .................. 95
Molecular Toxicology in Relation to Personalized Medicines ............... 95
Toxicogenomics .................................................................................. 95
Gene Expression Studies ..................................................................... 96
Genomics and the Prediction of Xenobiotic Toxicity ......................... 97
Pharmacogenetics in Clinical Trials ....................................................... 97
Clinical Implications of Pharmacogenetics ................................................ 98
Application of CYP450 Genotyping in Clinical Practice ................... 98
Genotype-Based Drug Dose Adjustment ............................................ 98