This document provides an overview of pharmacogenetics and pharmacogenomics. It defines the terms, discusses early examples showing the role of genetics in drug response, and models of inheritance. It also covers goals of the field, examples demonstrating clinical relevance like TPMT and CYP2D6, challenges with polygenic traits, and barriers to clinical implementation. While the field aims to optimize drug efficacy and safety based on genetics, it is noted that the impact of genetics is often complex and not yet clear enough for wide clinical use in many cases.
genetic polymorphism new Presentation.pptxRumaMandal5
Genetic polymorphism was formerly applied to variants occurring at a frequency greater than 1%.
Types: SNPs,Insertions or deletions
Pharmacokinetic variations and pharmacodynamics variations
Application on G6PD deficiency
Pharmacological implications of genetic polymorphism and PharmacogeneticsRumaMandal4
Genetic polymorphism is applied to variants occuring at frequency >1%
Pharmacogenetics is study of genetic variation on drug response.
Pharmacogenetic traits may be Pharmacogenetics and pharmacodynamic types
Pharmacogenomics deals with the influence of genetic variation on drug response by co-relating gene expression or polymorphism with a drug’s efficacy or toxicity.
INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References
genetic polymorphism new Presentation.pptxRumaMandal5
Genetic polymorphism was formerly applied to variants occurring at a frequency greater than 1%.
Types: SNPs,Insertions or deletions
Pharmacokinetic variations and pharmacodynamics variations
Application on G6PD deficiency
Pharmacological implications of genetic polymorphism and PharmacogeneticsRumaMandal4
Genetic polymorphism is applied to variants occuring at frequency >1%
Pharmacogenetics is study of genetic variation on drug response.
Pharmacogenetic traits may be Pharmacogenetics and pharmacodynamic types
Pharmacogenomics deals with the influence of genetic variation on drug response by co-relating gene expression or polymorphism with a drug’s efficacy or toxicity.
INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References
pharmacogenomics is a new drug discovry approach. It is the study of how genes affect a person's response to drugs, combining pharmacology and genomics
Genetic polymorphisms are variations in gene sequences that occur in at least 1% of the general population, resulting in multiple alleles or variants of a gene sequence.
The most commonly occurring form of genetic variability is the single nucleotide polymorphism (SNP, often called “snip”)
Pharmacogenomics: A new age drug technologyMahek Sharan
the pharmacogenomics require the pharmacology and genomic together to improve the drug responses and the new age drug potential according to individual need
Pharmacogenetics d and effect on determination of drug dosing in PharmacotherapyChiranjibBagchi1
Pharmacogenomics is a n upcoming issue in medicine and health which might be recognised as a future medicine.People might resort into genetic testing before being prescribed by a drug to optimise it,s efficacy and prevent toxicity.
Hence it definitely will have a personal, economical, societal, legal and ethical connotation and will not be restricted to merely a scientific and individual health related issue .So whole of the scientific fraternity and the medical and allied healthcareprofessional, legal system and political decision makers , drug manufacturers all should be held immensely responsible for future decision making to make decisions or creating guidelines and regulations to solicit the problems arising out of the application of new scientific discoveries based on Pharmacogenomics in future. Thus pharmacogenomics might come into a rescue for a particular group of persons benefitting out of the genetic testing in terms of successful drug therapy but others might deny testing for being marked to be a treatment orphan in the light of insurance providers. A mystereous and challenging situation might be awating for whigh the world human societyand community at large should get themselves prepared for.
Pharmacogenomics is a new trending branch which has created enormous hopes in improving diagnostic methods, treatment outcomes and preventing adverse events and therapeutic failures. In this ppt basics of pharmacogenomics and pharmacogenetics has been discussed in simplest possible way along with two case studies. Clinical applications of pharmacogenomics has also been discussed in brief.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stockrebeccabio
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stock
Telegram: bmksupplier
signal: +85264872720
threema: TUD4A6YC
You can contact me on Telegram or Threema
Communicate promptly and reply
Free of customs clearance, Double Clearance 100% pass delivery to USA, Canada, Spain, Germany, Netherland, Poland, Italy, Sweden, UK, Czech Republic, Australia, Mexico, Russia, Ukraine, Kazakhstan.Door to door service
Hot Selling Organic intermediates
pharmacogenomics is a new drug discovry approach. It is the study of how genes affect a person's response to drugs, combining pharmacology and genomics
Genetic polymorphisms are variations in gene sequences that occur in at least 1% of the general population, resulting in multiple alleles or variants of a gene sequence.
The most commonly occurring form of genetic variability is the single nucleotide polymorphism (SNP, often called “snip”)
Pharmacogenomics: A new age drug technologyMahek Sharan
the pharmacogenomics require the pharmacology and genomic together to improve the drug responses and the new age drug potential according to individual need
Pharmacogenetics d and effect on determination of drug dosing in PharmacotherapyChiranjibBagchi1
Pharmacogenomics is a n upcoming issue in medicine and health which might be recognised as a future medicine.People might resort into genetic testing before being prescribed by a drug to optimise it,s efficacy and prevent toxicity.
Hence it definitely will have a personal, economical, societal, legal and ethical connotation and will not be restricted to merely a scientific and individual health related issue .So whole of the scientific fraternity and the medical and allied healthcareprofessional, legal system and political decision makers , drug manufacturers all should be held immensely responsible for future decision making to make decisions or creating guidelines and regulations to solicit the problems arising out of the application of new scientific discoveries based on Pharmacogenomics in future. Thus pharmacogenomics might come into a rescue for a particular group of persons benefitting out of the genetic testing in terms of successful drug therapy but others might deny testing for being marked to be a treatment orphan in the light of insurance providers. A mystereous and challenging situation might be awating for whigh the world human societyand community at large should get themselves prepared for.
Pharmacogenomics is a new trending branch which has created enormous hopes in improving diagnostic methods, treatment outcomes and preventing adverse events and therapeutic failures. In this ppt basics of pharmacogenomics and pharmacogenetics has been discussed in simplest possible way along with two case studies. Clinical applications of pharmacogenomics has also been discussed in brief.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stockrebeccabio
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stock
Telegram: bmksupplier
signal: +85264872720
threema: TUD4A6YC
You can contact me on Telegram or Threema
Communicate promptly and reply
Free of customs clearance, Double Clearance 100% pass delivery to USA, Canada, Spain, Germany, Netherland, Poland, Italy, Sweden, UK, Czech Republic, Australia, Mexico, Russia, Ukraine, Kazakhstan.Door to door service
Hot Selling Organic intermediates
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
3. Pharmacogenetic versus
Pharmacogenomic
• No universally accepted definitions of either
• Often used interchangeably
• Pharmacogenetics used for more than 40 years to denote the science
about how heritability affects the response to drugs.
• Pharmacogenomics is new science about how the systematic identification
of all the human genes, their products, interindividual variation,
intraindividual variation in expression and function over time affects drug
response/metabolism etc.
• The term pharmacogenomics was coined in connection with the human
genome project
• Most use pharmacogenetics to depict the study of single genes and their
effects on interindividual differences in (mainly) drug metabolising
enzymes, and pharmacogenomics to depict the study of not just single
genes but the functions and interactions of all genes in the genome in the
overall variability of drugs response
4.
5.
6. Pharmacogenetics
• “Pharmacogenetics is the study of how
genetic variations affect the disposition
of drugs, including their metabolism and
transport and their safety and efficacy”
•J. Hoskins et. al NRC 2009
7. Pharmacogenetics involves both PK
and PD
• Pharmacokinetic
“The process by which a drug is absorbed,
distributed, metabolized, and eliminated by the
body”
• Pharmacodynamic
“the biochemical and physiological effects of drugs
and the mechanisms of their actions”
8. Goals of Pharmacogen(etics)omics
• Maximize drug efficacy
• Minimize drug toxicity
• Predict patients who will respond to
intervention
• Aid in new drug development
9. The Hope of Pharmacogenomics
• Individuals genetic makeup with allow
selective use of medications such that
– Efficacy maximized
– Side effect minimized
11. In the Beginning
• Mendelian genetics “single gene – single
disease”
– single wild type allele and single disease allele
– Patterns of inheritance included autosomal
dominant (need only one disease allele) and
autosomal recessive (need two disease alleles)
• Followed soon thereafter by additive (co-
dominant) model
– Both alleles contribute to phenotype
14. Empiric observations suggesting
Pharmacogenetics important
• Clinical response to many drugs varies widely
amongst individuals
• Same drug-> same dose -> same indication in
different individuals
– Some respond
– Some don’t
– Some don’t respond and have serious toxicity
16. The beginning of pharmacogenetics
• 1950s
– “Inheritance might explain variation in individuals
response and adverse effects from drugs”
Motulsty
– “Pharmacogenetics defined as “study of role of
Genetics in drug response” Vogel
– Most of studies for next several decades of “high
penetrance monogenic” gene-drug interactions
– Def: Monogenetic disease. Mutation at single
locus sufficient to result in disorder
17. Penetrance
• Penetrance of a disease-causing mutation is
the proportion of individuals with the
mutation who exhibit clinical symptoms.
– Eg. if a mutation in the gene responsible for a
particular autosomal dominantdisorder has 95%
penetrance, then 95% of those with the mutation
will develop the disease, while 5% will not.
18. Victor McKusick
• Established Online Mendelian Inheritance in
Man in early 80s
• Categorized majority of Mendelian Disorders
• Became very clear that there are many
different disease alleles for many disorders
(allelic heterogeneity)
• Recently many disorders have associated
modifier genes that modify disease phenotype
– Eg. Age-of-onset and severity
21. TPMT
• Main metabolizer of chemotherapeutic agents
6MP and azothiopurine (used mainly in blood
based malignancies)
• TPMT deficiency leads to severe toxicity
associated with treatment (potential
mortality)
25. FDA approved pharmacogenetic tests
Gene Drug Consequence
TPMT 6MP Toxicity
CYP2D6 Tamoxifen Decreased efficacy
UGT1A1 Irinotecan Toxicity
CYP2D6 Codeine Ineffective analgesia
These genes all modulate Pharmokinetics
26. Contribution of High Penetrance Monogenic Model to
PG
• Contribution likely not as large as initially
anticipated
• For most pharmacologic traits might be 15-20%
at most
– Could consider this penetrance
• Redundancy likely a major contributing factor
• MANY ENZYMES INVOLVED IN DRUG METABOLISM WITH
MANY ALTERNATE PATHWAYS
• Dichotomous disease versus quantitative trait
• Much more likely polygenic model with gene-
environment interactions
27. Some of it ain’t genetic
• Age
• Co-morbidities
• Renal and hepatic function (dysfunction)
• Concomitant medications
• Diet and smoking
28. Common Disease Common Variant
Hypothesis
• Most complex
diseases are
strongly
influenced by
combination of
frequent alleles
that each only
exert modest
effect
31. Polygenic Model and PG
• Elucidation unlikely possible before advances
in genomics
• Technologic advances
– High throughput sequencing of DNA
– Affordable genotyping of 100ks to 1-2M SNPs
• Genomic knowledge advances:
– Especially Human Genome Project and HapMap
Projects
32.
33.
34.
35.
36.
37.
38.
39. Cost of Genotyping
• In 2005 (5 years ago!)
– $1600 to genotype 250K SNPs in one individual
• 2009
– $250 to genotype >1Million SNPs
• 2014
-$200-250 to genotype >5 millions SNPs
40.
41.
42.
43. Hapmap project
• There are an estimated 10 million SNPs with
MAF >1%
• Hapmap project genotyped Chinese,
Japanese, African and European individuals
(families)
46. A more in depth look at PK in
clinical practice
Tamoxifen use and CYP2D6
47. Tamoxifen metabolism
• Needs to be converted to endoxifen to be
active
– catalysed by the polymorphic enzyme
cytochrome P450 2D6 (CYP2D6)
– 6-10% European population deficient in this
enzyme
• Efficacy of tamoxifen likely low in this population
• Suggests consider alterative treatments
49. About the CYPs
• Membrane bound enzymatic proteins
– Involved in oxidation, peroxidation and reductive
metabolism
– Responsible for >90% of drug transformation
• Greater than 50 different CYP genes encoding 50
different proteins
• CYP2D6 present mainly in liver and a major player
in drug metabolism from antidepressants to
antihypertensive to chemotherapy
50. Evolution of CYP nomenclature
• Initially astute clinical observation of unusual
drug response
• Such responses then found to be heritable
• Early example of phenotype to genotype
approach
• CYP2D6 polymorphism the first described
• Increasing recognition of poor metabolizer
phenotype occurred at time that genotyping
technology in evolution
52. CYP2D6 alleles
• There are >70 described in this gene
– Bottom line: variants either cause no change,
decrease somewhat, or significantly decrease
metabolism
• Extensive metabolizers ( EM), intermediate (IM)
metabolizers, and poor metabolizers (PM)
• EM is the standard metabolism allele against which
others are compared (consider it the wild type)
54. CYP2D6 alleles
Copy Number Variation
• Throughout the genome there are areas of
DNA that are represented in variable copies in
individuals (CNV)
• CYP2D6 is one such area
• Up to 16 copies seen in some individuals
– “NORMAL VARIANT”
• ULTRARAPID METABOLIZERS
55. Consequence of CYP2D6 alleles?
• EM/EM or EM/IM(PM) normal metabolizers
• IM/IM or IM/PM intermediate metabolizers
• PM/PM poor metabolizers
• Poor/(Intermediate) metabolizers have much
lower levels of endoxifen than intermediate/
rapid metabolizers
56. CYP2D6 Genotype and clinical
outcomes
• Several (small trials) have suggested
decreased efficacy of Tamoxifen in poor
(intermediate) metabolizers both in adjuvant
therapy and in treatment of metastatic
disease (see Hoskins NRC 2009 for details)
– All retrospective
– Largest was only statistically significant association
in univariate analysis
– In additions several trials have not confirmed
these results
57. Reasons for discordant results in
CYP2D6 trials
• Did not genotype many of the rarer poor
metabolizer alleles
• Did not account for concurrent use of other drugs
metabolized by CYP2D6 in many cases
• Different dose of Tamoxifen in several trials
• Did not assay endoxifen levels
• Power (poor metabolizers rare)
• Unknown variants in other genes whose products
involved in tamoxifen metabolism
58. So what is needed to clarify the issue of
relevance of CYP2D6 genotype and clinical
relevance?
• Large randomized trial that compares
standard dosing of tamoxifen to genotype
adjusted dosing
• Until that point clinical utility of testing
(commerically available) unclear
– Should recommend avoiding SSRIs that inhibit
CYP2D6 significantly (see later)
59. Provocative thoughts
• In post-menopausal breast cancer tamoxifen is
falling out of favor due to the efficacy of
Aromatase Inhibitors (inhibit extragonadal
production of estrogen)
– AI shows increased efficacy c/w tamoxifen
• BUT MUCH MORE EXPENSIVE AND DIFFERENT S/E PROFILE
• Some suggestion that increased efficacy of AI
completely explained by decreased efficacy of
Tamoxifen in CYP2D6 IM and PM
– Punglia (2008) JNCI
60. More relevant to pre-menopausal
woman
• Can’t use AI alone
• In poor metabolizer could consider
– Increased dose???
– Alternative estrogen receptor modulator not
metabolized by CYP2D6 (eg. raloxifen)
– Consider AI with ovarian ablation (chemical or
otherwise)
61. Ethnic Differences in IM and PM of
CYP2D6
• PM alleles more common in European
population
• IM alleles much more common in East Asian
and African population
– In East Asians Intermediate Metabolizers show
similar in vitro CYP2D6 activity c/w Poor
Metabolizers in European populations
• Gene-gene or gene-environment interactions
62. Drug Co-administration
• Antidepressant use common in breast cancer patients
– Depression more common in breast cancer patients and
antidepressant often used to treat how flashes associated with
tamoxifen use
• SSRIs (eg. Fluoxetine and paroxetine) inhibit CYP2D6
• Level of inhibition varies between different drugs with
paroxetine having most inhibition and venlafaxine causing
none
• Kelly et al. BMJ 2010
– Population based cohort study of women receiving tamoxifen
adjuvantly for treatment breast cancer
– Mortality from breast cancer increased in group
using paroxtetine concurrent with tamoxifen
63. Irinotecan – PK example in Colon Cancer
• Excreted after conjugation (glucuronidation) by UGT1A1
• TATA element (consists of TA repeats) in UGT1A1 promoter
shows correlation with transcription levels
– More repeats lower transcription levels
– An example of a non-SNP variant with clinical relevance
• Homozygosity for 7-repeat allele, also known as
UGT1A1*28 associated with severe toxicity (diarrhea and
low WBC counts mainly)
– Results have been somewhat inconsistent but meta-analysis
confirms same especially with higher doses of Irinotecan
– Homozygosity only in 5-15% of individuals
64. PD example in Colon Cancer Treatment
• EGFR inhibitors used in
treatment of advanced
colon cancer (eg.
Cetuximab)
• Tumors with k-RAS (and
probably BRAF)
mutations will NOT
respond to EGFR
inhibition
Nature Rev. Cancer July 2009
66. Effect of Clopidogrel as Compared with Placebo on Clinical Outcomes among Patients with
Acute Coronary Syndromes in the CURE trial, Stratified According to Metabolizer Phenotype.
Paré G et al. N Engl J Med 2010;363:1704-1714
67. Kaplan–Meier Curves for Event-free Survival According to CYP2C19 Loss-of-Function and
Gain-of-Function Allele Carrier Status among European and Latin American Patients with
Acute Coronary Syndromes in the CURE Trial.
Paré G et al. N Engl J Med 2010;363:1704-1714
68. Effect of Clopidogrel as Compared with Placebo on Clinical Outcomes among Patients with
Atrial Fibrillation in ACTIVE A, Stratified According to Metabolizer Phenotype.
Paré G et al. N Engl J Med 2010;363:1704-1714
69. Kaplan–Meier Curves for Event-free Survival According to CYP2C19 Loss-of-Function and
Gain-of-Function Allele Carrier Status among European Patients with Atrial Fibrillation in
ACTIVE A.
Paré G et al. N Engl J Med 2010;363:1704-1714
70. Baseline Characteristics of Genotyped Patients in the CURE and ACTIVE A Trials.
Paré G et al. N Engl J Med 2010;363:1704-1714
71. Why is pharmacogenomics not widely
utilized in the clinic
• It required a shift in clinician attitude and beliefs “not
one dose fits all”
• Paucity of studies demonstrating improved clinical
benefit from use of pharmacogenomic data
– Still much to be learned
• Even some of the black block warnings
currently on drug labels may be overcalls of
importance
• Genome wide interrogation will likely be important
to get the entire picture
72. Conclusion
• Genetic variation contributes to inter-individual differences
in drug response phenotype at every pharmacologic step
• Through individualized treatments, pharmacogenetics and
pharmacogenomics are expected to lead to:
• Better, safer drugs the first time
• More accurate methods of determining appropriate drug
dosages
• Pharmacogenomics offers unprecedented opportunities to
understand the genetic architecture of drug response
• HOWEVER IN MANY CASES NOT YET READY FOR PRIME
TIME!!!