The Busy Physician’s Guide To Genetics, Genomics and Personalized Medicine (eBook)

Foreword 8
Preface 10
Contents 12
Introduction 20
You Want to Provide Your Patients with the Best Care Possible… 20
…And This Book Can Help 21
A Great Deal of Work Remains, but the Principle Has Clearly Been Proven 22
The Necessary Infrastructure Is Evolving 23
Chapter 1: Genetic Variability Provides the Biochemical Basis for Our Individuality, Including Differences in Our Susceptibility to Many Common Diseases 26
1.1 Defining and Differentiating Between Genetics and Genomics 26
1.2 The Structure of DNA, the Variability of the DNA Sequence and the Independent Inheritance of Gene Alleles by Siblings 27
1.2.1 The Structure of DNA 27
1.2.2 The Arrangement of Genes on Chromosomes 30
1.2.3 The Polymorphic Human DNA Sequence: Gene Alleles, Protein Isoforms and Genotypes 33
1.2.4 Each Sibling Inherits a Unique Combination of Gene Alleles from the Parent 35
1.3 A Review of the Process Whereby a Gene Makes Its Protein 37
1.3.1 Coding Sequences and Regulatory Sequences 37
1.3.2 Transcription: Deoxyribonucleic Acid (DNA) Makes Ribonucleic Acid (RNA) 38
1.3.3 Posttranscriptional RNA Processing 38
1.3.4 Translation of mRNA into a Polypeptide 40
1.3.5 The Genetic Code and the Structures of Our Amino Acids 41
1.3.6 Posttranslational Processing of the Polypeptide 42
1.4 A Typical Gene’s Sequence and the Level of Activity in the Associated Protein Are as Variable as Any Other Human Trait 42
1.5 Risk-Increasing Alleles Have Variable Frequencies and Variable Levels of Penetrance 46
1.6 Polymorphisms in Promoter Regions and Other Non-coding Sequences Influence the Activity of Our Proteins 47
1.6.1 Polymorphisms in Promoter Regions Alter the Gene’s Level of Activity 47
1.6.2 Chromosome Rearrangements Can Cause Promoters to Drive Transcription of the Wrong Sequences 49
1.6.3 Intronic Gene Variants That Influence RNA Splicing or Gene Activity May Be Unrecognized Risk Factors 50
1.6.4 Intronic Polymorphisms Can Influence the Ratio of Protein Isoforms or the Balance of Allelic Expression 50
1.6.5 Interfering RNAs Exert an Important Influence over Gene Activity 51
1.7 Epigenetic Factors Also Control Gene Activity 52
1.8 Common Types of Variants in the Human DNA Sequence 54
1.9 Common Multifactorial Diseases Are Genetic Disorders, Despite Their Non-Mendelian Patterns of Inheritance 56
1.10 Personalized Medicine Testing May Allow You to Better Tailor the Treatment to the Individual, and May Allow the Individual to Make Healthier Choices 57
1.11 Summary 58
Further Readings 59
Chapter 2: Making the Most of Family History Information, Single Gene Disorders and Mendelian Patterns of Inheritance, and When to Refer to a Genetic Specialist 60
2.1 Maximizing the Use of Family Medical History in Disease Risk Assessment 60
2.2 Single Gene Disorders 62
2.3 Understanding Mendelian Patterns of Inheritance (Single Gene Disorders) 63
2.3.1 Autosomal Dominant Inheritance 64
2.3.2 Autosomal Recessive Inheritance 65
2.3.3 X-Linked Recessive 66
2.3.4 X-Linked Dominant Inheritance 67
2.3.5 Y-Linked Inheritance 68
2.4 Assessing the Risk of Recurrence in Mendelian Pedigrees 69
2.5 Carrier Frequencies for the More Common Recessive Single-Gene Disorders 70
2.6 Referring to a Genetic Specialist 71
2.7 New Genomic Applications for Complex Disease Will Change Approaches to Genetic Counseling and Personalized Medicine 72
Selected References 74
Chapter 3: Types of Genetic Tests and Issues Associated with the Interpretation of Their Results 75
3.1 Accessing Current Information on Available Personalized Medicine Tests 75
3.2 Standard Format for Genetic Test Results 77
3.3 Risk-Increasing Gene Alleles Often Have Limited Penetrance 79
3.4 The ACCE and EGAPP Projects Evaluate Emerging Genetic Tests 80
3.5 Assessing the Usefulness of a Genetic Test 81
3.6 Even an Informative Genetic Test May Have Limited Clinical Utility 83
3.7 Single Nucleotide Polymorphisms (SNPs) Are the Most Commonly Tested Polymorphisms 83
3.8 There Are Many Small Deletions and Insertions in Different People’s DNA 84
3.9 Repeated Sequence Length Polymorphisms and Microsatellite Analysis 85
3.9.1 The Repeated Sequence Motif Can Vary in Length 85
3.9.2 Microsatellite Instability (MSI) Is Observed in Certain Types of Cancer 86
3.9.3 Loss of Heterozygosity (LOH) of Microsatellites Is Seen in Several Disorders 87
3.10 Chromosome Rearrangements Can Contribute to Some Complex Disorders 88
3.11 Copy Number Variation Is Surprisingly Frequent 88
3.12 It Is Sometimes Necessary to Determine the Level of Activity in Specific Genes 88
3.13 Mitochondrial DNA Variants Are Also Relevant 89
3.14 Many Epigenetic Factors That Influence Gene Activity Are Amenable to Testing 89
3.15 Some Tests Assess Characteristics of the Pathogen 90
3.16 Cancer Analyses Often Must Include Somatic Mutations as well as Germline Mutations 90
3.17 Predictive Algorithms Must Include both Genetic and Nongenetic Factors 90
3.18 Genome-Wide Association (GWA) Studies Provide Insights into the Mechanisms for Disease, But Their Results Are Often Not Clinically Useful 91
3.18.1 Direct-to-Consumer GWA Testing Services May Provide Results That Have Limited Clinical Utility 91
3.18.2 GWA Studies Identify Risk-Increasing Alleles, But Have Their Limitations 91
3.18.3 Measures of the Association Between the Risk-Influencing Allele and the Disorder/ADR 93
3.18.4 Many of the SNPs That Are Used in GWA Studies Are Not Themselves Functional Polymorphisms, But Are Linked to Functional Polymorphisms 94
3.18.5 Haplotype Blocks in the Human Genome Increase the Efficiency of GWA Studies 96
3.18.6 Internet Resources That Summarize Findings from GWA Studies 97
3.19 A Brief Introduction to the Most Important Technological Advances 98
3.19.1 The Polymerase Chain Reaction (PCR) Allows One to Isolate the Sequence of Interest Many Assays Begin with the PCR98
3.19.2 Microarray Analyses Have Greatly Accelerated the Pace of Discovery 99
3.19.3 Sequencing Provides Maximum Information, and Will Revolutionize Clinical Diagnostics 100
3.19.4 There Are Several Techniques Commonly Used to Assess Status for a SNP 101
3.19.5 PCR Simplifies Analysis of Indels and Length Polymorphisms and Detection of MSI and LOH 102
3.19.6 Hybridization Techniques Detect CNVs 102
3.19.7 Reverse Transcription-PCR Measures the Level of Activity in a Gene 104
3.19.8 Immunohistochemical (IHC) Analyses Allow Direct Visualization of the Protein 104
3.19.9 Expression Arrays Reveal Disease-Associated and Treatment-Associated Changes in Gene Expression 105
3.19.10 Some Epigenetic Factors Can Be Easily Assessed 106
3.19.11 G-Banding Allows the Detection of Chromosome Rearrangements 106
Further Readings 107
Chapter 4: Toward the Safer and More Effective Use of Prescription Drugs: Pharmacogenetics 108
4.1 Genetic Polymorphisms Affect Both the Pharmacokinetics and Pharmacodynamics of Many Prescription Drugs 109
4.2 Improving on the Disease-Oriented Approach to Prescribing Drugs 111
4.3 Limitations of Genetic Testing 116
4.4 Dose-Calculating Algorithms Must Take Genetic and Nongenetic Factors into Account 118
4.5 Epigenetic Factors Must Be Factored into Many Algorithms as Well 120
4.6 Polymorphisms in the CYP450 Genes Influence the Pharmacokinetics of Many Commonly Prescribed Drugs 121
4.6.1 The CYP450 Enzymes Metabolize Many Commonly Prescribed Drugs 121
4.6.2 Defining the Metabolizer Phenotype by Assessing CYP450 Status 121
4.7 Other Functional Polymorphisms That Affect the Pharmacokinetics of Multiple Drugs 124
4.7.1 N-Acetyltransferase 2 124
4.7.2 Butyrylcholinesterase 125
4.7.3 Functional Polymorphisms in Drug Transporter Genes also Affect the Response to Many Drugs 125
4.8 Polymorphisms in the Genes Encoding Beta-Adrenergic Receptors Influence the Pharmacodynamics of Beta-Blockers 127
4.9 Keeping up to Date with FDA Approvals and the Status of the Field 128
Further Readings 129
Chapter 5: Taking a Personalized Medicine Approach to Breast and Colon Cancer 130
5.1 Cancer Is a Complex Genetic Disease 130
5.2 Breast Cancer Gene Variants with Low Penetrance 132
5.3 Further Research Will Increase Accuracy and Standardize Risk-Estimating Algorithms 133
5.4 Useful Online Programs to Calculate Breast Cancer Risk 135
5.5 Highly Penetrant Breast Cancer Gene Variants 136
5.6 Hereditary Breast-Ovarian Cancer Syndrome 137
5.7 BRCA Gene Testing 139
5.8 Effects of Possessing Risk-Increasing BRCA Alleles 141
5.9 Cancer Screening and Prevention Measures for Female BRCA Variant Carriers 142
5.10 BRCA Mutation Positive Case Study 143
5.10.1 Mrs. C’s Initial Meeting with the Genetic Counselor 145
5.10.2 Interpreting the Test Results and Following Them Up 146
5.10.3 The Plans for Mrs. C and Her Family Members 148
5.10.4 Further Developments 149
5.11 Colon Cancer Gene Variants with Low Penetrance 149
5.12 Highly Penetrant Colorectal Cancer Gene Variants 150
5.13 Lynch Syndrome 150
5.14 Molecular Genomic Testing in Patients Suspected of Having Lynch Syndrome 152
5.14.1 Microsatellite Instability (MSI) Is a Hallmark of Lynch Syndrome 152
5.14.2 Some Labs Offer Complementary MSI and IHC Analyses 153
5.15 Cancer Screening and Prevention Measures for LS Mutation Carriers 154
5.16 Familial Adenomatous Polyposis 154
5.17 APC Mutation Screening in Familial Adenomatous Polyposis 155
5.18 Cancer Screening and Prevention Measures for APC Mutation Carriers 156
5.19 Personalizing Drug Therapy for Cancer Patients 157
5.19.1 Gene Expression Assays can Classify Cancers into Molecular Subtypes 157
5.19.2 Several Gene Polymorphisms Affect Activity in Signal Transduction Pathways 158
5.19.3 Glioblastomas with MSH6 Mutations Resist Alkylating Agents 160
5.19.4 Pharmacokinetically Relevant Gene Polymorphisms Influence Drug Response, Especially the Risk for ADRs 160
5.19.5 HLA Type May Influence the Risk for Hypersensitivity Reactions After Abacavir 162
Further Readings 162
Chapter 6: Personalizing Risk Assessments and Treatments for Complex Cardiovascular Disease 163
6.1 Cardiovascular Diseases Are Complex, Multifactorial Diseases with Highly Variable Phenotypes 163
6.2 Family History and CVD Risk 165
6.3 Useful Online Programs to Estimate Heart Disease Risk 166
6.4 CVD-Associated Gene Variants Have Been Particularly Difficult to Identify 167
6.5 Most CVD-Associated Gene Variants Have Low Penetrance 168
6.5.1 A Cluster of Linked Markers in 9p21.3 Are Associated with Several CVDs 168
6.5.2 Other Low-Penetrance Variants That Influence Risk for CVD 170
6.6 Low-Penetrance Gene Variants That Affect Predisposing Phenotypes 171
6.6.1 Low-Penetrance Gene Variants That Alter Blood Lipid Levels 171
6.6.2 Sodium/Potassium Regulation and Essential Hypertension 171
6.6.3 Cardiac Channelopathies 172
6.6.4 Variants That Influence the Inflammation Response Influence Risk for CVDs 174
6.6.5 Genetic Variants Influence the Level of Oxidative Stress 174
6.6.6 Plasma Homocysteine Levels Influence Risk for CVD 175
6.6.7 Knowing They Possess Low-Penetrance Variants May Motivate Patients’ Behavior 175
6.7 Case Report – Genetic Testing in a Patient with Type 2 Diabetes (T2D) and a Family History of Myocardial Infarction (MI) 175
6.7.1 Jameer’s Initial Visit 176
6.7.2 Meeting with the Cardiologist and Genetic Counselor 177
6.7.3 The Plan for Follow-Up 179
6.8 CVD Gene Variants with High Penetrance: Familial Hypercholesterolemia (FH) 179
6.8.1 FH Is Often Underdiagnosed 180
6.8.2 Highly Penetrant FH Gene Variants 180
6.9 Molecular Genomic Testing in Patients Suspected of Having FH 183
6.10 CVD Gene Variants with High Penetrance: Hypertrophic Cardiomyopathy (HCM) 183
6.10.1 The HCM Phenotype Is Highly Variable 183
6.10.2 Highly Penetrant Gene Variants That Increase Risk for HCM 184
6.11 Therapy and Prevention Measures for HCM Mutation Carriers 186
6.12 Genes Influencing the Risk for Other Cardiomyopathies 186
6.13 Cardiovascular Pharmacogenomics 187
6.13.1 The CYP450 Enzymes Metabolize Several Drugs That Are Prescribed for CVDs 187
6.13.2 The Pharmacogenomics of Cholesterol-Lowering Drugs 188
6.13.3 Pharmacogenomic Testing Is Particularly Important for Patients Taking Warfarin 191
6.13.4 The Pharmacogenomics of Antihypertensive Drugs 192
6.13.5 Plasma Homocysteine Levels Influence Pyridoxine Response 193
6.13.6 CYPC19 Testing for Patients Prescribed Clopidogrel 193
Further Readings 193
Chapter 7: Other Multifactorial Disorders for Which Genetic/Genomic Testing Is Providing Insights 195
7.1 Age-Related Macular Degeneration 195
7.2 Type 2 Diabetes 196
7.2.1 GWA Studies Have Identified Several Genetic Markers That Increase Risk for T2D 197
7.2.2 The Currently Available Predictive Tests Do Not Include Genetic Markers 199
7.2.3 The Pharmacogenomics of Type 2 Diabetes 199
7.3 Personalizing the Approach to Psychiatric Disorders 200
7.3.1 Many Original Findings Must Be Confirmed 200
7.3.2 Testing Genetic Variants That Influence Pharmacokinetics Is Helpful in the Treatment of Some Psychiatric Disorders 201
7.3.3 Some Associations with Attention Deficit-Hyperactivity Disorder (ADHD) Have Been Confirmed 201
7.3.4 Polymorphisms in Genes That Influence Serotonergic and Dopaminergic Function May Influence Personality 202
7.3.5 Copy Number Variation May Influence the Risk for Schizophrenia 202
7.3.6 Several Polymorphisms May Influence the Risk for Schizophrenia and the Response to Antipsychotic Drugs 203
7.3.7 Several Polymorphisms Have Been Associated with Depression and Bipolar Disorder (BPD) 203
7.3.8 Polymorphisms in the Serotonin Transporter (5HTT) Gene May Not Influence One’s Risk for Depression After All 205
7.3.9 Polymorphisms in the Monoamine Oxidase a (MAOA) Gene May Not Influence the Propensity toward Antisocial Behavior after All 208
7.3.10 Anxiety Disorders 208
7.4 Personalizing the Treatment for Substance Abuse 208
7.4.1 Most Studies Have Focused on Catecholamine and Opiate Pathways 208
7.4.2 Stimulants 209
7.4.3 Alcohol 211
7.4.4 Opiates 212
7.4.5 Nicotine 213
7.5 Alzheimer Disease and Cognitive Decline in Aging 214
7.5.1 The ApoE Gene Is a Known Risk Factor 215
7.5.2 Other Gene Variants That Influence the Risk for AD and Cognitive Decline in the Elderly 215
7.6 Asthma and Other Respiratory Disorders 218
Further Readings 220
Epilogue and List of Resources 221
Personalized Genomic-Based Medicine Is Here to Stay, But Challenges Remain 221
Resources to Help You Keep up to Date with the Status of the Field and Further Your Education 224
Further Readings 225
Incorporating Personalized Medicine into Practice 225
Interpreting Genome-Wide Association Studies 226
How to use an article about genetic association (three part JAMA series) 226
Databases Containing Information About Variants Associated with Diseases 226
Preventive Health Guidelines 226
Educational Web Resources 226
Ethical, Legal and Social Issues 227
Index 228