This document provides an introduction to pharmacogenomics. It defines pharmacogenomics as the study of how genetic variations affect drug response and metabolism. It discusses key concepts like interracial and individual variability in drug metabolism due to single nucleotide polymorphisms and variable number tandem repeats. Case studies on tamoxifen metabolism and alcohol metabolism are presented. Challenges to implementing pharmacogenomics in clinical practice are noted. Applications to drug development and personalized medicine are mentioned.
3. INTRODUCTION:
• Often used interchangeably with pharmacogenetics
• Pharmacogenetics 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.
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4. Pharmacogenetics(omics)
• “Pharmacogenetics is the study of how genetic
variations affect the disposition of drugs, including
their metabolism and transport and their safety and
efficacy”
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6. Some basic concepts.....
• Interracial variability in drug response and
metabolism
• Individual variability in drug response and
metabolism
• Variation in drug response and metabolism is due to
two main factors
1. Variation in number of recurring small sequences which
occur among the non-coding junk DNA called as VNTR’s
(Variable number tandem repeats)
2. SNP’s (Single nucleotide polymorphisms)
These variations can be understod by
a) Pharmacokinetic variability
b) Pharmacodynamic variability
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7. PK varibility:
• It refers to variability in drug disposition
• As of know pharmacogenomics allows us to concentrate
on interracial and individual variability solely.
• But previously it was believed that changes in
metabolism was involved in PK variability
• Now various insights such as SNP’s led to think us that
SNP’s affect receptors resulting in altered drug efficacy
• Since SNP’s are ever incrasing ,it can be concluded that
1. Every individual handles drug differently
2. And optimisation of such therapy is done only by prior genetic
testing
3. This refers to PERSONALIZED MEDICINE
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8. Example-several variants in single gene
• over 70 variants in the CYP2D6 gene have been described, some of
which lead to loss of function.
• Homozygotes, which comprise 7% of Caucasian and African-
American populations, are rendered so-called 'poor metabolizers'
• Such loss-of-function are very uncommon among Asian populations
• At the other end of the catalytic spectrum are individuals with
multiple functional copies of the gene, known as 'hyper-extensive
metabolizers', who constitute up to 20% of some African
populations.
• Drugs whose biotransformation to inactive metabolites is CYP2D6
dependent cause side effects more often among poor
metabolizers, and lack of efficacy among hyperextensive
metabolizers.
• This is one of the challenges in contemporary pharmacogenomic
analysis. 8
9. PD variability
• pharmacodynamic mechanisms could contribute a second important
component to variable drug actions
• pharmacodynamic variability can arise from two distinct mechanisms
1. Drug exerts a variable effect
Example :
a) the APOE GENOTYPE determines the extent of choline acetyltransferase expression, and has
been linked to the response to therapy with tacrine
b) A similar phenomenon is observed in patients who are exposed to drugs that prolong the QT
INTERVAL on a surface electrocardiogram (an effect that, if exaggerated, can lead to fatal cardiac
arrhythmias)
2. The second, more generic, form of pharmacodynamic variability is
the variability of the broader biological context
Example :-beta blockers have been shown to be especially beneficial in a
group of patients at high risk of heart failure who are homozygous for an intronic
deletion in the (ACE) gene (the DD genotype), which encodes a key enzyme in the
renin–angiotensin system50,51
, even though -blockers do not act directly on the ACE
gene
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11. • Variability in drug action can also arise through the
pharmacodynamic mechanisms :
• first, the drug might interact with several other targets;
• second, there might be variability in the function or
expression level of the drug target;
• or third, other molecules might modulate the biological
context within which the drug–target interaction takes
place.
• DNA variants in elements that control each of these
processes can lead to variable drug actions
• More generally, each POLYMORPHISM that mediates
the development or severity of a human disease can be
viewed as a candidate for modulating the responses of
drugs that are used to treat that disease. 11
12. Goals of Pharmacogen(etics)omics
• Maximize drug efficacy
• Minimize drug toxicity
• Predict patients who will respond to
intervention
• Aid in new drug development
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13. The Hope of Pharmacogenomics
• Individuals genetic makeup with allow
selective use of medications such that
– Efficacy maximized
– Side effect minimized
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15. HOW STUDY IS DONE???
• The first step is to identify a phenotype of interest
• This is ordinarily a clinically important end point
— which can be a beneficial drug effect or a serious adverse effect
— that has considerable inter-individual variability with no 'obvious' cause
• When the phenotype is a variable physiological trait or expression of
disease, the next step is often to conduct epidemiological studies
• The second step is to accumulate patients (and their DNA) with the
defined phenotype, along with control subjects.
• The third step in the algorithm is to identify genes, or sets of genes
• Finally identifying the polymorphism in the candidate gene and refining
the phenotype
• The main advantage of such an approach is that genes or pathways that
are unidentified at present may be implicated in mediating drug
responses.
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18. TPMT:
• Thiopurine-methyltransferase deficiency (TPMT)
predicts BONE MARROW APLASIA during exposure to 6-
mercaptopurine ,a treatment for childhood leukaemia.
• Although many variants that can cause this adverse drug
effect have been identified, they are rare
• In this instance, a clinically important but rare allelic
variant was identified
• There are considerable ethical issues involved in large-
scale attempts to characterize the genetic basis of
human physiology, pathology and response to drugs
• For instance, characterizing drug responses in defined
ethnic groups might carry with it a risk of stigmatization.18
20. • HapMap data provides a rich source of highly
differentiated SNPs for design of admixture panels
• The International HapMap Project was aimed to
develop a haplotype map(HapMap) of the human
genome, to describe the common patterns of human
genetic variation.
• used to find genetic variants affecting health, disease
and responses to drugs and environmental factors
• Haplotypes are generally shared between populations,
but their frequency can differ widely. Four populations
were selected for inclusion in the HapMap:
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21. • 30 adult-and both parent, Nigeria (YRI),
• 30 trios of Utah residents of northern and western
European ancestry (CEU),
• 44 unrelated Japanese individuals from Tokyo, Japan
(JPT) and
• 45 unrelated Han Chinese individuals from Beijing,
China (CHB)
• To obtain enough SNPs to create the Map, they discover
millions of additional SNPs.
• By comparison, at the start of the project, fewer than 3
million SNPs were identified, and no more than 10% of
them were known to be polymorphic
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24. 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
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26. Alcohol Metabolism
• Alcohol gets metabolised into acetaldehyde amd acetate
• When the concentration of acetaldehyde builds up in the body it leads to
serious adverse effects
• The enzyme Acetaldehyde dehydrogenase(ALDH*2) converts alcohol into
acetaldehyde
• But in some asian origins its seen that alcoholism leads to flushing
• When a detailed study was conducted it was found that humans have a
gene called ALDH*2 which codes specifically for enzyme ALDH*2
• The enzymatic polymorphisms of this enzyme are responsible for variable
effects of alcohol in different populations
• Also if patient is homozygous ,the enzyme will be non functional and leads
to serious effects
• If heterozygous then poor metabolism of alcohol followed by some
flushing response
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27. Why is pharmacogenomics not widely
utilized in the clinic
• It requires 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
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28. APPLICATIONS
• Used in aproval and evaluation of various
drugs
• Drug interactions
• In estimations of labelling implications
• Personalized medicine
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29. 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!!!
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