Post on 15-Jul-2015
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Pharmacogenomics and its
significance
Devi Lekshmi S
2013-11-192
Department of Plant
Biotechnology
Major Advisor,
Dr. P A Nazeem
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OutlinePharmacogenomics
Genes and enzymes involved in drug
metabolism
Variants and SNPs
Role of bioinformatics in pharmacogenomics
Clinical significance of pharmacogenomics
Personalized medicine
Benefits and challenges
Significance in plants
Conclusion
Pharmacogenomics :
pharmacology +
genomics
How genetic variation
influences drug action
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Pharmacogenomics
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…pharmacogenomics
Different platforms
Human Genome Project (2001-2003)
International HapMap Project (2003)
1000 Genomes Project (2010 onwards))
(Carr et al., 2014)
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Pharmacogenetics (Friedrich Vogel) often used
interchangeably with pharmacogenomics
Pharmacogenetics focus on single drug-gene
interaction
Pharmacogenomics- a more genome-wide association
approach incorporating genomics and epigenetics
Pharmacogenetics and
pharmacogenomics
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Genes involved in drug metabolism
PK genes and PD genes
Pharmacokinetics (PK)
- “what the body does to the drug”
Pharmacodynamics (PD)
- “what the drug does to the body”
PK genes encode proteins involved in
ADME of drug
(Altman et al., 2012)
Enzymes involved in drug metabolism
• Cytochrome P450
enzymes (<20)
Clinical drugs metabolized by
one or more cytochrome P450
enzymes
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(Ma and Lu, 2011)
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Cytochrome P450 enzymes
a) CYP2D6
Metabolism of 20-25% of marketed drugs
Polymorphism best studied
Drugs: antidepressants, antipsychotics
b) CYP2C19
More than 20 polymorphism reported
Eg: CYP2C19*2, *3
Drugs: antiulcerative, anticonvulsant
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c) CYP3A4/5
Most abundant
Seen in human liver
Metabolism of more than 50% of drugs
20 variants identified
Eg: CYP3A4*16, CYP3A4*2CYP3A4*7
…cytochrome P450 enzymes
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Polymorphism of drug transporters
1. ABCB1 genes
Encode P-glycoprotein : transporter
protein
SNP C3435T occurs most frequently
Effects metabolism of drug statin
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…polymorphism of drug transporters
2. ABCG2 genes
Breast Cancer Resistance Protein (BCRP)
Polymorphism adversely affect disposition of
anticancerous drugs
Eg: Rosuvastatin
(Hesselink et al., 2003)
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How variants formed ?
SNP and addition, deletion, duplication of
nucleotide bases
Single nucleotide polymorphism - most common
variation
14 million SNP identified in human genome
60,000 SNPs are located in the coding region
Certain SNPs associated with drug efficacy
(Alwi, 2005)
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…SNP and drug efficacy
Statin- highly effective in reducing risk of
cardiovascular and cerebrovascular events
MDR1 gene helps in metabolism of drug
50 SNP were reported
3 main SNPs C3435T, G2677T/A, C1236T
Reduced bioavailability of statins
(Babu et al., 2012)
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Role of bioinformatics
Interdisciplinary field – develop methods and
tools for understanding biological data
Reduces time to interpret the data
Many bioinformatic tools and databases to help
pharmacogenomics
(Satendra et al., 2010)
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Bioinformatic tools and databases
Retrieval of data from databases
(Uniprot Knowledge Database )
Multiple sequence alignment using clustalW2
server
- To identify the identical, similar and different
regions in the sequences
- To generate phylogenetic tree
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Basic Local Alignment Search Tool (BLAST)
• Widely used for searching regions of similarity
between biological sequence
To compute the potential effects of SNP on RNA
structure use SNPfold
PolyPhen tool used for assessment of variants-
• Predict the functional effects of aminoacid changes
using 3D statistical models
…bioinformatic tools and databases
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…bioinformatic tools and databases
Pharmacogenomics Knowledge Base
(PharmGKB)
Information about variants
Interpret evidence behind each variant
Genes in which variants found
Variants influencing the drug
<http://www.pharmgkb.org>
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Warfarin:
significant problems for humans
Company director died- brain
hemorrhage
Warfarin effect: cause of the
death
(Brutlag, 2014)
David Belk, July 2,
2008
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Significance in cardiology
Anti thrombotic drugs : warfarin and clopidogrel
Oral coumarin anticoagulants (OCAS)
Enzymes influence OCAS dose response
1. CYP2C9- metabolizes OCAS
2. VKORC1- target for two drugs
(Ventola, 2011)
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…significance in cardiology
CYP2C9*2 and *3 variants inhibit the metabolism of
OCAS
VKORC1 – 1639G >A influences pharmacodynamic
response to coumarins
Improper metabolism- ADR
FDA – optimized drug dose for patients identified
with above variants either one or both
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Oncology
Human epidermal growth factor receptor 2
HER+3 variant - high level of HER2
Over expression – breast cancer
HER2 expression variability- Trastuzamb
treatment
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Diagnostics in pharmacogenomics
Highly accurate diagnostic tests are
available
First diagnostic- BRAC1: Myriad genetics
(1997)
Use high throughput technologies
(Daniel et al., 2014)
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Biomarker Disease Drug Assay
Kit
Technology
HER2 gene
amplification
Breast
cancer
Trastuzumab SPOT-
Light
HER2
CISH
CYP2C19
variants+
Depressi
on
Atomoxetine Roche
Amplichip
CYP450
test
FISH
Invitro diagnostic tests by FDA
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Biomarker Indication Drug Assay Kit Technology
EGFR
protein
expression
Colorectal
cancer
Cetuximab
`
EGFR
pharmDx
IHC
KRAS
mutation
Colorectal
cancer
Cetuximb Therascreen Real-time
PCR
…invitro diagnostic tests by FDA
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Personalized medicine
(Verma, 2012)
Prescription of drugs based on patients genetic
profile
Reduce speculation in drug prescription
Increases the confidence of both physicians and
patients
Every patient is different, we need to
individualize every patients therapy
Lung cancer
Victor- lung cancer (2010)
Too advanced stage for
radiation
Genetic mutation- ALK gene
ALK- Anaplastic Lymphoma
Kinase
37(www.uchospitals.edu/specialties/cancer/patient-
stories /victor-lung)
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… lung cancer
Discovered EML4-Alk gene in 2007
Pfizer, the company developed drug to block gene
Drug: Gizotinib
Prescribed dosage
CAT result: shrunken tumour and not producing
any new growth spots
Angelina Jolie Effect
On February 16, 2013 Jolie
underwent double mastectomy
Family tree warranted
genetic testing for BRCA
mutation
Found out 87% of risk in
developing cancer
Mastectomy lowered this risk
to under 5%
39(www.breast-cancer-research.com/content/16/5/442)
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…Angelina Jolie Effect
Mutation in BRCA1 and BRCA2 shows 45 to
90% chance to develop breast cancer
Jolie’s announcement in media, increased
number of women preferred for testing
A positive celebrity effect- Angelina Jolie Effect
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Benefits
Identification of diseases related to genes and specific
drugs- more drug specific cure
Categorizing of human diseases at genome level
Can adopt primary and secondary preventive
measures
Maximal patient care and minimum ADR
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1. Ethical issues
Privacy of the study subjects
- Individuals
- Family
May not be affordable for a common man
- Developing countries
- Subsidized by government
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2. Legal issues
What is the legal liability if the genetic data is
lost ?
How much the doctor is obliged to inform the
person?
What is the legal issue for job discrimination?
(Bansal et al., 2005)
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Significance in plants
Pharmacogenomic enzymes: significant role in plants
Plants are exposed to toxic compounds
Eg: Herbicides, insecticides and pollutants
Detoxification: P450 enzymes and ABC transporters
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Detoxification by plants
Plant CYP enzyme Herbicide
(Substrate)
H. tuberosus CYP76B1 Phenylureas
Soybean CYP71A10 Phenylureas
Tobacco CYP81B2,
CYP71A11
Chlortoluron
(Kumar et al., 2012)
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Phytoremediation
Using transgenic plants for herbicide metabolism
Uses cytochrome P450 genes from plants and
human
Transgenic rice encoding human genes
- CYP1A1, CYP2B6, CYP2C19
Showed more tolerance to atrazine and diuron
A promising field in near future
(Kawahigashi, 2009)
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Conclusion
A boon for medical fraternity
Unravels the genetic basis of individual
variability in drug response
Not well studied and exploited in plants
Right drug, in right dose for the
right patient at right time