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Anaesthesiology
Genomic Basis of Perioperative Precision Medicine
Built from Barash Clinical Anesthesia, 9th Edition
What’s inside
16 sections · 198 slides
Overview
- Scope of this presentation
Scientific Rationale for Perioperative Precision Medicine
- Variability in response to surgery
- The perioperative exposome
- Phenotypes affected by this variability
- Gene and environment interaction around surgery
- Threshold model and physical resilience
- Sources of genomic contribution to risk
- Perioperative genomics and the perioptome
- Definition of precision medicine
- Three converging opportunities
- The All of Us Research Program
- Why the perioperative period suits precision medicine
- Electronic health records in perioperative care
- Pharmacogenomic decision support across the surgical journey
- Aim of precision perioperative medicine
- Three cogs of future implementation
Human Genomic Variation
- Polymorphisms as the common form of variation
- Structural genetic variants
- Categories of common human genetic variation
- Reading the figure: genetic vocabulary
- Functional consequences of a single nucleotide polymorphism
- The mitochondrial genome
- Completing the human genome sequence
- Archaic human ancestry and disease susceptibility
- ACMG classification and actionable secondary findings
Profiling the Regulatory Genome
- The central dogma of molecular biology
- Increasing complexity of the central dogma
- Gene expression profiling
- Static and dynamic genomics
- Tools for measuring dynamic genomic change
- Thoracic aortic disease: static genomics in practice
- Subphenotypes and endotypes
- Reported endotypes and subphenotypes
- Molecular response to cardiac surgery with and without bypass
- Myocardial gene expression during ischaemia
- Genomic signatures of preconditioning
- Transcriptome versus proteome
- Proteomics
- Proteomics of hibernation and organ protection
- Metabolic phenotypes
- The phenotypically augmented patient journey
- Metabolic signature of planned myocardial infarction
- Metabolic profiling in cardiac surgery
- Metabolic phenotyping in other surgical settings
- Pharmacometabonomics
- Multiomics analysis
- Single-cell mass cytometry after surgery
- Preoperative immune phenotype and recovery
- Distinguishing marker from mechanism
- Reading the gene and protein expression studies table
- Gene and protein expression studies with implications for perioperative and critical illness outcomes
- Gene and protein expression studies with implications for perioperative and critical illness outcomes (continued)
- Gene and protein expression studies with implications for perioperative and critical illness outcomes (continued)
- Gene and protein expression studies with implications for perioperative and critical illness outcomes (continued)
- Gene and protein expression studies with implications for perioperative and critical illness outcomes (continued)
Epigenetics
- Definition of epigenetics
- Components of the epigenetic code
- Epigenetics of pain
- Epigenetic control of stress responses
- Circulating cell-free nucleic acids
- Cell-free DNA in oncologic and cardiac surgery
- Donor-derived cell-free DNA in transplantation
Genetic Epidemiology and Functional Genomic Methodology
- Genetic association studies
- The candidate gene approach
- Outcomes studied by candidate gene association
- The genome-wide scan
- Perioperative outcomes studied by genome-wide association
- Projects that enabled genome-wide association studies
- The missing heritability problem
- Small effect size does not mean small therapeutic gain
- Regulatory variants and expression quantitative trait loci
- Cis and trans expression quantitative trait loci
- Polygenic risk scores
- Whole-exome sequencing
- Study design for rare variant discovery
- First clinical whole-genome analysis
- Limitations of genetic association studies
- Clinical actionability, validity and utility
- The Clinical Genome Resource
Genomics and Perioperative Risk Profiling
- Burden of surgery in the United States
- Projected growth in surgical burden
- Thromboinflammation as a target
- Four interaction domains with genomic variability
- Categories of perioperative phenotypes
- Categories of perioperative phenotypes
Predictive Biomarkers for Perioperative Adverse Cardiac Events
- Limits of multifactorial cardiac risk indices
- Pathophysiology of postoperative myocardial infarction
- Inflammatory gene variants and postoperative myocardial infarction
- Variants amplifying the inflammatory response to bypass
- Inflammatory variants in peripheral vascular surgery
- C-reactive protein as a cardiovascular risk marker
- Added value of C-reactive protein over clinical scores
- Genetic control of C-reactive protein levels
- Polygenic risk scores for inflammation
- Cytokine storm syndrome
- Reappraising anticytokine strategies in cardiac surgery
- Haemostatic changes after surgery
- The coagulation continuum after cardiac surgery
- Plasminogen activator inhibitor-1 gene variation
- Platelet variants in noncardiac surgery
- Factor V Leiden and perioperative outcome
- B-type natriuretic peptide biology
- Natriuretic peptides and perioperative outcome
- Preoperative BNP in cardiac surgery
- Sympathetic activation and adrenergic receptor variants
- Genetic variation in vascular responsiveness
- Vasoplegic syndrome
- Pulmonary vascular tone in congenital cardiac surgery
- Endothelial biomarkers after cardiac surgery
- Beta-2 adrenergic receptor variants in noncardiac surgery
- The 9p21 locus
- Genome-wide findings for postoperative myocardial infarction
- Biology implicated by the new infarction loci
- Polygenic risk score for coronary disease and myocardial injury
- Genetic polymorphisms and polygenic risk scores in adverse perioperative cardiovascular events (part 1)
- Genetic polymorphisms and polygenic risk scores in adverse perioperative cardiovascular events (part 2)
Perioperative Atrial Fibrillation
- Burden of perioperative atrial fibrillation
- The chromosome 4q25 locus
- Candidate pathways for postoperative atrial fibrillation
- Inflammation and postoperative atrial fibrillation
- Innate immunity and the first genome-wide study of atrial fibrillation
- Adrenergic pathway genes and beta-blocker response
- Polygenic risk score for atrial fibrillation after cardiac surgery
- Ventricular-like gene signature in fibrillating atria
- Expression quantitative trait analysis of postoperative atrial fibrillation
Genetic Variants and Postoperative Event-Free Survival
- Genes associated with long-term outcome after bypass grafting
Genetic Susceptibility to Adverse Perioperative Neurologic Outcomes
- Incidence of neurologic morbidity after cardiac surgery
- Impact and unexplained variability of neurologic injury
- Pathophysiology of perioperative neurologic injury
- Variants protective against postoperative cognitive decline
- Apolipoprotein E and cerebral outcome after cardiac surgery
- Apolipoprotein E in infants
- Platelet glycoprotein variants and neurologic outcome
- Genomic response to bypass in cognitive decline
- Biomarkers and cerebral lesions after carotid endarterectomy
- Genetic polymorphisms in adverse perioperative neurologic events
Kidney and Lung Outcomes
- Incidence and impact of acute kidney injury after cardiac surgery
- Candidate gene findings in postoperative kidney injury
- Genome-wide findings for kidney injury after cardiac surgery
- Angiotensin-converting enzyme variant and lung outcome
- Surgical technique and genetic risk for lung outcome
- Genetic polymorphisms in other adverse perioperative outcomes
Pharmacogenomics and Anesthesia
- Definition of pharmacogenomics
- Pharmacokinetic and pharmacodynamic variability
- Pharmacokinetic and pharmacodynamic determinants of drug response
- Plasma pseudocholinesterase deficiency
- Variability in anaesthetic potency
- Receptors unlikely to mediate anaesthetic immobility
- Proteomic search for anaesthetic targets
Genetic Variability in Pain Response
- Heritability of pain and nociceptive sensitivity
- The mu-opioid receptor locus
- Melanocortin 1 receptor and gene-by-sex interaction
- Pain sensitivity as a clinical predictor
- Cytochrome P450 2D6 and analgesic efficacy
- Distribution of CYP2D6 metabolic phenotypes
- Codeine and the poor metabolizer phenotype
- Polygenic scores in opioid use disorder
Genetic Variability in Response to Other Perioperative Drugs
- Drug-metabolising enzyme families
- Ondansetron failure in ultrarapid metabolizers
- Cytochrome P450 2C9
- Available pharmacogenomic tests
- Genotype-guided preoperative warfarin interruption
- Genetic variation in drug targets
- Ion channel variants and drug-induced long QT syndrome
- Reading the perioperative drug polymorphism table
- Genetic polymorphisms involved in variable responses to drugs used in the perioperative period
- Genetic polymorphisms involved in variable responses to drugs used in the perioperative period (continued)
- Integrating genotype into the electronic health record
- Pharmacometabonomics as a complement
Conclusions and Future Directions
- A new framework for the cycle of innovation
- Phenotypes that need standard definitions
- What genomics could offer the anaesthetist
- Ethical concerns in personal genomics
- Transferability of genetic tests across ethnic groups
- Deliverables of the precision perioperative approach
- Key points of this topic
- Most promising biomarkers at present
- About these references
- References
- References (continued)
- References (continued)
- References (continued)
- Barash, Cullen, and Stoelting's Clinical Anesthesia, 9th Edition