Pharmacogenomics in Drug Discovery and Development

Preface
Contents
Contributors
Chapter 1: Target Discovery for Drug Development Using Mendelian Randomization
1 Introduction
2 Mendelian Randomization
2.1 Mendelian Randomization Terms
2.2 Mendelian Randomization Assumptions and Limitations
2.3 Mendelian Randomization Exposures
2.4 Mendelian Randomization Outcomes
2.5 Mendelian Randomization for Drug Repurposing and Adverse Event Screening
2.6 Mendelian Randomization Analysis Methods
3 Methods
3.1 Obtain Genetic Instruments
3.2 Extract Exposure gIVs from Outcome GWAS and Harmonize
3.3 Perform MR Analysis
3.4 Diagnostics and Sensitivity Analysis
4 Notes
References
Chapter 2: Human Leukocyte Antigen (HLA) Testing in Pharmacogenomics
1 Introduction to the Human Leukocyte Antigen (HLA) System
1.1 Class I
1.2 Class II
1.3 HLA Genetics
2 HLA Nomenclature
3 Examples and Mechanisms of HLA-Associated Adverse Drug Reactions
3.1 HLA and Adverse Drug Reactions (ADR)
3.2 Mechanisms
4 Overview of HLA Typing Methods
4.1 Typing by Sequence-Specific Primers (PCR-SSP)
4.2 Typing by Sequence-Specific Oligonucleotide Probes (PCR-SSO)
4.3 Sequencing-Based Typing (SBT)
4.4 Testing for Presence or Absence of Specific Alleles
4.4.1 Monoclonal Antibody Technique
4.4.2 Real-Time PCR
4.4.3 Targeted Genotyping Using Linkage Disequilibrium
4.5 Imputing HLA Types Using SNP Data from Genome-Wide Association Studies (GWAS)
5 Conclusions
References
Chapter 3: Pharmacogenomics in Targeted Therapy and Supportive Care Therapies for Cancer
1 Introduction
2 Pharmacogenomics in Targeted Therapies
2.1 Bevacizumab
2.2 EGFR-Targeted Tyrosine Kinase Inhibitors
2.3 BCR-ABL Targeted Tyrosine Kinase Inhibitors (TKIs)
2.4 Immune Checkpoint Inhibitors
2.5 Trastuzumab
2.6 Vascular Endothelial Growth Factor (VEGF) Inhibitors
2.7 Tamoxifen
3 Pharmacogenomics in Drugs Commonly Used to Manage Chemotherapy Side Effects
3.1 Allopurinol
3.2 Rasburicase
3.3 5-HT3 Antagonists
4 Conclusion
References
Chapter 4: Pharmacogenomics in Cytotoxic Chemotherapy of Cancer
1 Introduction
2 Pharmacogenomics in Cytotoxic Chemotherapy
2.1 Azathioprines
2.2 Anthracyclines
2.3 Irinotecan
2.4 Taxanes
2.5 Methotrexate
2.6 Platinums
2.7 Fluoropyrimidines
2.8 Asparaginase
3 Conclusion
References
Chapter 5: Management of Side Effects in the Personalized Medicine Era: Chemotherapy-Induced Peripheral Neurotoxicity
1 Introduction: Pharmacogenomics and CIPN: What and Why?
1.1 The Identikit
1.2 Issues in CIPN
2 CIPN and Pharmacogenomics So Far
2.1 The GSTP1 Gene Saga: Starting Point Away from Peripheral Nervous System
2.2 An Opposite Approach: Starting from Peripheral Nervous System
3 Future Perspectives: Crosstalk Between Bench and Bedside
References
Chapter 6: The Yin-Yang Dynamics in Cancer Pharmacogenomics and Personalized Medicine
1 Challenges in Cancer Pharmacogenomics and Personalized Medicine
2 Complex Adaptive Systems (CAS) in Cancer
3 Yin-Yang Dynamics in CAS and Cancer
4 Yin-Yang Dynamics and miRNAs in Cancer
5 The Yin and Yang in Epigenetics and Cancer
6 Yin-Yang Dynamics in Cytokines and Chemokines
7 The Yin and Yang of Immune Cells: Inflammation and Tumor Microenvironments
8 Yin-Yang Dynamical Balances in the Redox Systems
9 The Yin-Yang Interactions in Autophagy and Apoptosis
10 Yin-Yang Dynamical Balances in the p53 and c-Myc Pathways
11 Yin-Yang Interactions in Various Networks
12 Conclusion: Yin-Yang Dynamics and Personalized Cancer Therapy
References
Chapter 7: Design of Personalized Neoantigen RNA Vaccines Against Cancer Based on Next-Generation Sequencing Data
1 Introduction
2 Methods
2.1 NGS Technologies for Cancer Vaccine Development
2.1.1 Sequencing Technology for Personalized Medicine
2.1.2 NGS for Neoantigen Vaccine Development
2.1.3 NGS for Variant Detection or Somatic Mutation Calling
2.1.4 NGS for HLA Typing
2.1.5 Integrated Pipelines
2.1.6 NGS Challenges for Neoantigen Vaccine Development
2.2 Neoantigen Selection
2.2.1 Somatic Single Nucleotide Variants
2.2.2 Human Leukocyte Antigen (HLA) Haplotyping
2.2.3 Predicting Peptide Processing
2.2.4 MHC Ligandome Prediction
2.3 mRNA Cancer Vaccines
2.3.1 Production of mRNA Cancer Vaccines
2.4 Formulation and Delivery Strategies
2.4.1 RNA Vaccine Formulation
2.4.2 Cell-Targeted Delivery
2.4.3 Administration Routes
2.5 Immunogenicity Assessment
2.5.1 Measures to Assess In Vivo Antigen-Specific Immunity
2.5.2 Measures to Assess In Vitro Antigen-Specific Immunity
3 Notes
References
Chapter 8: COVID-19 Pharmacotherapy: Drug Development, Repurposing of Drugs, and the Role of Pharmacogenomics
1 Introduction
2 COVID-19 Therapeutic Methods
2.1 Antiviral Drug Therapy
2.2 Immunotherapy
2.2.1 Convalescent Plasma
2.2.2 Monoclonal Antibodies
2.2.3 Vaccines
3 Repurposing Drugs for COVID-19
4 Pharmacogenomics
5 Design Considerations for a Pharmacogenomic Assay
References
Chapter 9: Pharmacogenomics Informs Cardiovascular Pharmacotherapy
1 Introduction
2 Hypertension Therapy
2.1 Thiazide Diuretics
2.2 Beta-Blockers
2.3 Renin-Angiotensin-Aldosterone System (RAAS)
2.4 Angiotensin-Converting Enzyme (ACE) Inhibitors
2.5 Angiotensin Receptor Blockers (ARB)
2.6 Direct Renin Inhibitors
2.7 Hydralazine
3 Cholesterol Medications
4 Acute Coronary Syndrome (ACS) Medications
5 Anticoagulants
5.1 Warfarin
5.2 Dabigatran
5.3 Rivaroxaban
5.4 Apixaban
5.5 Edoxaban and Betrixaban
6 Antiplatelets
6.1 Clopidogrel
6.2 Prasugrel, Ticagrelor
7 Aspirin
8 Digoxin
References
Chapter 10: Pharmacogenomic Screening of Drug Candidates using Patient-Specific hiPSC-Derived Cardiomyocyte High-Throughput Ca...
1 Introduction
2 Materials
2.1 Cell Preparation
2.2 Recording Ca2+ Transients
2.3 Analysis
3 Methods
3.1 Cell Preparation
3.2 Scan
3.3 Analysis
4 Notes
References
Chapter 11: The Yin-Yang Dynamics in Cardiovascular Pharmacogenomics and Personalized Medicine
1 Introduction: Yin-Yang Dynamics in Complex Cardiovascular Diseases
2 Yin-Yang Dynamics in Atherosclerosis and Cardiovascular Pharmacogenomics
3 Yin-Yang Dynamics at Various Systems Levels and Stages in Heart Failure
4 Dynamical Yin-Yang Balances in Thrombosis and Cardiovascular Homeostasis
5 Yin-Yang Dynamics in Hypertension, Arrhythmias, Stroke, and Various Networks
6 Conclusion and Future Studies: Yin-Yang Dynamics in Personalized Medicine for CVDs
References
Chapter 12: GTPγS Assay for Measuring Agonist-Induced Desensitization of Two Human Polymorphic Alpha2B-Adrenoceptor Variants
1 Introduction
2 Materials
2.1 Plasma Membrane Preparation
2.2 GTPγS Assay
3 Methods
3.1 Plasma Membrane Preparation from Excised Adrenal Glands
3.2 GTPγS Assay Protocol
4 Notes
References
Chapter 13: Pharmacogenomics of Alzheimer´s Disease: Novel Strategies for Drug Utilization and Development
1 Introduction
2 Phenotypic Profile
3 Concomitant Disorders
4 Alzheimer´s Disease Therapeutics and Drug Development
5 Immunotherapy
6 Pharmacogenomics
6.1 The Pharmacogenomic Machinery in Alzheimer´s Disease
6.2 Pathogenic Genes
6.3 Mechanistic Genes Involved in Cholinergic Neurotransmission
6.4 Metabolic Genes
6.5 Transporter Genes
6.6 Pharmacogenetics of Acetylcholinesterase Inhibitors
6.6.1 Donepezil
6.6.2 Galantamine
6.6.3 Rivastigmine
6.6.4 Huperzine A
6.7 Pharmacogenetics of Memantine
6.8 Pharmacogenetics of Aducanumab
6.9 Pharmacogenetics of Multifactorial Treatments
6.10 Pharmacoepigenetics
6.11 Pharmacogenomics of Mood Disorders and Anxiety
7 Influence of Pharmacogenomic Factors on Adverse Drug Events
8 Future Trends
9 Conclusions
References
Chapter 14: Pharmacogenetics of Antipsychotic Treatment in Schizophrenia
1 Introduction
2 Pharmacogenetics of Antipsychotic Response
2.1 Pharmacokinetic Candidates in Antipsychotic Response
2.1.1 CYP2C19
2.1.2 CYP2D6
2.1.3 CYP1A2
2.1.4 CYP3A4
2.1.5 ABCB1
2.2 Pharmacodynamic Candidates in Antipsychotic Response
2.2.1 DRD2
2.2.2 DRD3
2.2.3 GRM7
2.2.4 KCNH7
2.2.5 HTR1A
2.2.6 HTR2A
2.2.7 HTR2C
2.2.8 HTR6
2.2.9 5HTT
2.2.10 COMT
2.2.11 GLP1R
2.2.12 GNB3
2.2.13 BDNF
2.2.14 ZNF804A
2.3 Genome-Wide Association Studies (GWAS)
2.4 Summary of Pharmacogenetics of Antipsychotic Metabolism and Response
3 Pharmacogenetics of Antipsychotic-Induced Side Effects
3.1 Antipsychotic-Induced Weight Gain
3.1.1 HTR2C
3.1.2 MC4R
3.1.3 LEP
3.1.4 BDNF
3.2 Antipsychotic-Induced Tardive Dyskinesia
3.2.1 CYP2D6
3.2.2 DRD2
3.2.3 DRD3
3.2.4 HTR2A
3.2.5 COMT
3.2.6 HSPG2
3.2.7 VMAT2
3.3 Clozapine-Induced Agranulocytosis
3.4 Other Side Effects
3.5 Summary of Antipsychotic-Induced Adverse Effects
4 Clinical Perspectives
4.1 Pharmacogenetic Testing in Schizophrenia Treatment
4.1.1 AmpliChip CYP450 Test
4.1.2 DMET Plus Solution
4.1.3 GeneSight
4.1.4 Genecept Assay
4.1.5 PGxPredict: Clozapine
4.2 Access to Pharmacogenetic Tests
4.3 Future Directions
5 Conclusion
References
Chapter 15: The Pharmacogenetic Impact on the Pharmacokinetics of ADHD Medications
1 Introduction
2 Methods
3 Discussion
3.1 Methylphenidate and CES1
3.2 Atomoxetine and CYP2D6
3.3 Mixed Amphetamine Salts and CYP2D6
3.4 Guanfacine and CYP3A4/5
3.5 Clonidine and CYP2D6
4 Notes
References
Chapter 16: Pharmacogenetics of Addiction Therapy
1 Introduction
2 Pharmacogenetics
3 Genetics
4 Drugs of Abuse and Dopamine System
5 Dopaminergic System Genes
5.1 Dopamine Receptor D2 (DRD2)/Ankyrin Repeat and Kinase Domain-Containing 1 (ANKK1) Genes
5.2 Dopamine Receptor D4 (DRD4) Gene
5.3 Dopamine β-Hydroxylase (DBH) Gene
5.4 Dopamine Transporter (SLC6A3) Gene
6 Opioidergic System Genes
6.1 μ-Opioid Receptor (OPRM1) Gene
6.2 δ-Opioid Receptor (OPRD1) Gene
6.3 κ-Opioid Receptor (OPRK1) Gene
7 Serotonergic System Genes
7.1 Serotonin Transporter (SLC6A4) Gene
7.2 Tryptophan Hydroxylase 2 (TPH2) Gene
7.3 Tetraspanin 5 (TSPAN5) Gene
8 Other Genes with Variants Associated with Pharmacotherapeutic Response
8.1 ATP-Binding Cassette, Subfamily B (MDR/TAP), Member 1 (ABCB1) Gene
8.2 α1A-Adrenoceptor (ADRA1A) Gene
8.3 Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (Beta Polypeptide) (NGF) Genes
8.4 β-Arrestin 2 (ARRB2) Gene
8.5 Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) and Subfamily B, Polypeptide 6 (CYP2B6) Genes
8.6 Gamma-Aminobutyric Acid Type B Receptor Subunit 1 (GABBR1) Gene
8.7 GATA Binding Protein 4 (GATA4) Gene
8.8 Glutamate Ionotropic Receptor Kainate-Type Subunit 1 (GRIK1) Gene
8.9 Methylenetetrahydrofolate Reductase (MTHFR) Gene
8.10 Myocardin (MYOCD) and Glutamate Receptor Metabotropic 6 (GRM6) Genes
8.11 Nectin Cell Adhesion Molecule 4 (NECTIN4) Gene
8.12 Potassium Inwardly Rectifying Channel, Subfamily J, Member 6 (KCNJ6) Gene
9 Conclusions
References
Chapter 17: Pharmacogenomics of Opioid Treatment for Pain Management
1 Introduction
2 Individual Genetic Differences to Opioids
3 Opioid Pharmacodynamics
4 Opioid Pharmacokinetics
5 Opioids to Treat Pain
5.1 Codeine
5.2 Fentanyl
5.3 Hydrocodone
5.4 Hydromorphone
5.5 Meperidine
5.6 Methadone
5.7 Morphine
5.8 Oxycodone
5.9 Oliceridine
6 Conclusion
References
Chapter 18: The Role of Pharmacogenomics in Postoperative Pain Management
1 Introduction
2 Pharmacogenetic Factors That Affect Postoperative Pain
2.1 Environmental Factors
2.2 Biological Factors
2.3 Psychological Factors
2.4 Genetic Factors
2.5 Ethnic Factors
3 Pharmacogenomics and Postoperative Pain Management
4 Acetaminophen
5 Lidocaine
6 Codeine
7 Morphine
8 Tramadol
9 Hydrocodone
10 Oxycodone
11 Diamorphine
12 Fentanyl
13 Buprenorphine
14 Ketamine
15 Remifentanil
16 Escitalopram
17 Conclusion
References
Chapter 19: Pharmacogenetics of Drug Therapies in Rheumatoid Arthritis
1 Introduction
2 Pharmacogenetics of Drugs in RA
2.1 Pharmacogenetics of Methotrexate
2.1.1 Transporter Genes: RFC1/GGH/ABCB1
2.1.2 ABCB1
2.1.3 MTHFR/DHFR/FPGS/TYMS
2.1.4 CCND1/ATIC
2.2 Pharmacogenetics of Azathioprine
2.3 Pharmacogenetics of Sulfasalazine
2.4 Pharmacogenetics of Biologics
2.4.1 Tumor Necrosis Factor Antagonists
TNF Gene Polymorphisms
TNF Receptor Polymorphisms
MHC Gene Polymorphisms, TNF, and MHC Microsatellites
RA Risk Variants
Cytokines, Toll-Like Receptors, and Signaling Pathways
Fcγ Receptor Variants
GWAS Studies
2.4.2 Rituximab
2.4.3 Tocilizumab
3 Conclusions and Future Directions
References
Chapter 20: Pharmacogenomics in Children
1 Children and Genetics
2 Sources of Variation in Drug Response in Children
2.1 Ontogeny as a Source of Drug Response Variation
2.2 6-Mercaptopurine and Codeine: A Tale of Two Drugs
3 Pharmacogenomics and Childhood Cancer
4 Personalized Medicine for Children
5 Ethical Issues
6 Pharmacogenomics and Drug Development for Children
References
Chapter 21: Genetic Ancestry Inference for Pharmacogenomics
1 Introduction
2 Materials
2.1 Operating Systems
2.2 Package Manager and Environment Management System
2.3 PLINK
2.4 ADMIXTURE
2.5 Genomic Variant Data
2.6 Genomic Sample Information
2.7 Programming
3 Methods
3.1 Software Installation
3.2 Download Genomic Variant Data
3.3 Download Genomic Sample Information
3.4 Extract Samples from the Four Populations to Be Analyzed
3.5 Linkage Disequilibrium (LD) Pruning
3.6 PCA Analysis
3.7 Visualize PCA Results
3.8 Admixture
3.9 Visualize ADMIXTURE Results
4 Notes
References
Index