1.
Pharmacogenomics
Dr. N. Anand Kumar,
Department of Biotechnology,
Vignan University

2.
Pharmacogenomics: DNA, Drugs & Dosage
 The human body is incredibly complex and the effects of a drug or medication can vary greatly between people
• What works for one person, may not be as effective for others or may cause side effects
• This variation can be due to many factors, like differences in age or size, your overall health or interactions with
other medications you might be taking
• Another key factor that can affect how you respond to a drug or medication is variation in your genes
• The study of the interaction between your genes and medications is called pharmacogenomics. It is study of genes
and their effects on medications
• An example of this is a gene called CYP2D6
• CYP2D6 makes a protein responsible for breaking down many different medications including the pain killer
codeine

3.
• When CYP2D6 breaks down codeine, it converts it into another molecule, morphine which
relieves pain
• Some people have a variant in the CYP2D6 gene that causes it to be less active
• When these people, known as poor metabolisers, take codeine, it doesn’t get converted to
morphine as efficiently
• This mean that the medication may be less effective at relieving pain
• Other people have a variant in CYP2D6 that causes them to convert codeine to morphine too
quickly
• In these people, known as rapid or ultrarapid metabolisers, even normal doses of codeine can
cause too much morphine to build up in the body
• This means they might be at an increased risk of side effects

4.
• One of the aim of pharmacogenomics is to understand whether people are poor or rapid
metabolisers for certain medications
• This information could help your doctor to prescribe the medications that will work best for you,
at the right dose, with less trail and error
• Pharmacogenomics information can be relevant throughout a persons lifetime
• Each time you need to take a new medication your doctor could refer to your genetic information
to see if the medication might be less effective than expected or if you might be at an increased
risk of side effects
• “ Everyone is unique. Pharmacogenomics looks at our differences on a genetic level, to determine
which drug therapies will be most effective and help us all stay healthy ”

5.
 Pharmacogenomics leads to a better understanding of interaction of drugs and organisms.
 The promise of pharmacogenomics is that both the choice of a drug and its dose will be
determined by the individual genetic make-up leading to personalized, more efficacious and less
harmful drug therapy.
 The techniques of genomics and proteomics help to understand disease and to discover new drug
targets.
 Finally, genomics allows to study the effects of drugs on gene expression.
 The limitations of pharmacogenomics are the complexities of gene regulation, of proteomics, of
gene-environment interactions and also of the psychological complexities of interactions between
physicians and patients.

6.
Pharmacogenetics – The Roots of Pharmacogenomics
 An ideal drug is one that effectively treats or prevents disease and has no adverse
effects.
 However, a medication is rarely effective and safe in all patients.
 Therefore, when a physician determines the dose of a drug, it is always a compromise
between “not too high” and “not too low” for this patient or group of patients.
 Dealing with diversity in drug effects is a major problem in clinical medicine and
in drug development.
 The size of the problem is considerable.
 A meta-anaylsis of 39 prospective studies from U.S. hospitals suggests that 6.7% of in-patients
have serious adverse drug reactions and 0.32% have fatal reactions, the latter causing about
100,000 deaths per year in the USA

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 Of equal relevance is the fact that most presently approved therapies are not effective in all patients.
 For instance, 20–40% of patients with depression respond poorly or not at all to antidepressant drug
therapy, and similar or even higher percentages of patients are resistant to the effects of
antiasthmatics, antiulcer drugs, to drug treatment of hyperlipidemia and many other diseases.
 The individual risk for drug inefficacy or drug toxicity is a product of the interaction of genes and
the environment.
 Environmental variables include nutritional factors, concommittantly administered drugs, disease
and many other factors including lifestyle influences such as smoking and alcohol consumption.
 These factors act in concert with the individual’s genes that code for pharmacokinetic and
pharmacodynamic determinants of drug effects such as receptors, ion channels, drug-metabolizing
enzymes and drug transporters.

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 Pharmacogenetics deals with inherited variations in drug effects.
 It carries the promise of explaining how the individual’s make-up of genes determines drug
efficacy and toxicity.
 Pharmacogenetics had its beginnings about 40 years ago when realized that some adverse drug
reactions could be caused by genetically determined variations in enzyme activity.
 For example, prolonged muscle relaxation after suxamethonium was explained by an inherited
deficiency of a plasma cholinesterase, and hemolysis caused by antimalarials was recognized as
being associated with inherited variants of glucose-6-phosphate dehydrogenase.
 Similarly, inherited changes in a patient’s ability to acetylate isoniazid was found to be the cause
of the peripheral neuropathy caused by this drug.

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 Genetic deficiencies of other drug-metabolizing enzymes such as cytochromes P450 CYP2D6,
CYP2C9, CYP2C19 or methyltransferases were discovered later.
 Most recently, it was realized that drug receptors, e.g., the 2-adrenoceptor, and drug transporters, e.g., the
multidrug resistance gene MDR1, are subject to genetic variation.
 Adverse drug reactions in individual subjects and members of their families often were the clinical events
that revealed genetic variants of these and other drug-metabolizing enzymes or drug targets.
 All these observations dealt with variations of specific genes or polymorphisms.
 Genetic polymorphisms are monogenic variations that exist in the normal population in a frequency of more
than 1%.
 One reason for the pre-occupation of pharmacogenetics with single genes is that they were easier to study
with the classical genetic techniques and many of them were clinically important.
 However, as will be discussed below, most differences between people in their reactions to drugs are
multigenic and multifactorial.

10.
 Molecular genetics and genomics have transformed pharmacogenetics in the last decade.
 The two alleles carried by an individual at a given gene locus, referred to as the genotype, can now
easily be characterized at the DNA level, their influence on the kinetics of the drug or a specific
receptor function, the phenotype, can be measured by advanced analytical methods for metabolite
detection or by sophisticated clinical investigations, e.g., receptor density studies by positron
emission tomography.
 Molecular studies in pharmacogenetics started with the initial cloning and characterization of the
drug-metabolizing enzyme CYP2D6 and now have been extended to numerous human genes,
including more than 20 drug-metabolizing enzymes and drug receptors and several drug transport
systems (www.sciencemag.org/feature/data/1044449.shl).
 Genotyping and phenotyping tests to predict dose requirements are now increasingly introduced
into preclinical studies of drugs and into the clinical routine, e.g., in the choice and initial dose
determination of antidepressants

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 Another important aspect of pharmacogenetics is the realization that all pharmacogenetic variations
studied to date occur at different frequencies among subpopulations of different ethnic or racial
origin.
 For instance, striking cross-ethnic differences exist in the frequency of slow acetylators of isoniazid
due to mutations of N-acetyltransferase NAT2, of poor metabolizers of warfarin due to mutations of
CYP2C9 and of omeprazole due to polymorphism of CYP2C19, and of ultrarapid metabolizers due
to duplication of CYP2D6 genes.
 Some of the mutations of these genes indeed occur uniquely in certain ethnic subpopulations and
trace the origins and movements of populations on this planet.
 This ethnic diversity, also called gene geography, pharmacoanthropology or ethnopharmacology,
implies that population differences and ethnic origin have to be considered in pharmacogenetic studies
and in pharmacotherapy.

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Observations of person-to-person differences in the metabolism of drugs and
consequently in drug kinetics and response led to the concepts of pharmacogenetics.
The same principal concepts apply to the genetic variability in the reaction
to food components (e.g., lactose intolerance) or to environmental toxins (e.g.,
carcinogens).
These fields often are termed “ecogenetics” and “toxicogenetics”.

13.
Pharmacogenomics – It is Not Just Pharmacogenetics
 Genomics involves the systematic identification of all human genes and gene products,
the study of human genetic variations, combined with changes in gene and protein
expression over time, in health and disease.
 Genomics is revolutionizing the study of disease processes and the development and
rational use of drugs.
 Its promise is to enable medicine to make reliable assessments of the individual risk to
acquire a particular disease, improve the classification of disease processes and raise the
number and specificity of drug targets.
 In 2001, almost the entire human genome sequence became principally known and the
information is increasingly accessible.

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 Moreover, in association with the public and private efforts to sequence the human genome, a
large number of techniques and bioinformatic tools have been developed.
 The term pharmacogenomics reflects the evolution of pharmacogenetics into the study of the
entire spectrum of genes that determine drug response, including the assessment of the
diversity of the human genome sequence and its clinical consequences.
 There are three aspects of pharmacogenomics that make it different from classical
pharmacogenetics.
1. Genetic Drug Response Profiles
2. The Effect of Drugs on Gene Expression
3. Pharmacogenomics in Drug Discovery and Drug Development

15.
Heading
Text

16.
Genes
• Genes are functional units of heredity as they are made of DNA
• The chromosome is made of DNA containing many genes
• Every gene comprises of the particular set of instructions for a particular function or protein-coding.
• Speaking in usual terms, genes are responsible for heredity
• There are about 30000 genes in each cell of the human body
• DNA present in the gene comprises only 2 percent of the genome.
• Many studies have been made on the same that found the location of nearly 13000 genes on each of
the chromosomes

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Characteristics determined by Genes
• The human cell contains 23 pairs of chromosomes.
• The trait is one of the characteristics determined by one or more genes.
• Abnormal genes and genes that are formed due to new mutations also result in certain traits.
• Genes vary in size depending on the code or the protein they produce.
• All cells in the human body contain the same DNA.
• The difference between the cells occurs due to the different type of genes that are turned on and
therefore produce a variety of proteins.

18.
Reasons for hereditary
• Genes come in pairs in the same way as the chromosomes.
• Each parent of a human being carries two copies of their genes and each parent passes
one copy of genes to their child.
• This is the reason why the child has many characteristics of both the parents like hair
colour, same eyes etc.

19.
Functions of Genes
1.Genes control the functions of DNA and RNA.
2.Proteins are the most important materials in the human body which not only help by being the building
blocks for muscles, connecting tissue and skin but also takes care of the production of the enzyme.
3.These enzymes play an important role in conducting various chemical processes and reactions within the
body. Therefore, protein synthesis is responsible for all activities carried on by the body and are mainly
controlled by the genes.
4.Genes consist of a particular set of instructions or specific functions. For example, the globin gene was
instructed to produce haemoglobin. Haemoglobin is a protein that helps to carry oxygen in the blood.

20.
DNA
• Nucleic acids are the organic materials present in all organisms in the form of DNA or RNA.
• These nucleic acids are formed by the combination of nitrogenous bases, sugar molecules and phosphate groups that
are linked by different bonds in a series of sequences.
• The DNA structure defines the basic genetic makeup of our body.
• In fact, it defines the genetic makeup of nearly all life on earth.
• “DNA is a group of molecules that is responsible for carrying and transmitting the hereditary materials or the
genetic instructions from parents to offsprings.”
• DNA is known as Deoxyribonucleic Acid. It is an organic compound that has a unique molecular structure. It is found in
all prokaryotic and eukaryotic cells

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DNA comprises a sugar-phosphate backbone and the nucleotide bases (guanine, cytosine, adenine and thymine).

22.
DNA Structure
• The DNA structure can be thought of as a twisted ladder.
• This structure is described as a double-helix.
• It is a nucleic acid, and all nucleic acids are made up of nucleotides.
• The DNA molecule is composed of units called nucleotides, and each nucleotide is composed of three different
components such as sugar, phosphate groups and nitrogen bases.
• The basic building blocks of DNA are nucleotides, which are composed of a sugar group, a phosphate group, and a
nitrogen base. The sugar and phosphate groups link the nucleotides together to form each strand of DNA. Adenine
(A), Thymine (T), Guanine (G) and Cytosine (C) are four types of nitrogen bases.

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• These 4 Nitrogenous bases pair together in the following
way: A with T, and C with G. These base pairs are
essential for the DNA’s double helix structure, which
resembles a twisted ladder.
• The order of the nitrogenous bases determines the genetic
code or the DNA’s instructions.
• Among the three components of DNA structure, sugar is
the one which forms the backbone of the DNA molecule.
• It is also called deoxyribose. The nitrogenous bases of the
opposite strands form hydrogen bonds, forming a ladder-
like structure

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• The DNA molecule consists of 4 nitrogen bases, namely adenine (A), thymine (T), cytosine (C) and Guanine (G),
which ultimately form the structure of a nucleotide.
• The A and G are purines, and the C and T are pyrimidines.
• The two strands of DNA run in opposite directions.
• These strands are held together by the hydrogen bond that is present between the two complementary bases.
• The strands are helically twisted, where each strand forms a right-handed coil, and ten nucleotides make up a
single turn.
• The pitch of each helix is 3.4 nm. Hence, the distance between two consecutive base pairs (i.e., hydrogen-bonded
bases of the opposite strands) is 0.34 nm.

25.
• The DNA coils up, forming chromosomes, and each chromosome has a single molecule of DNA in it.
• Overall, human beings have around twenty-three pairs of chromosomes in the nucleus of cells.
• DNA also plays an essential role in the process of cell division.

26.
How does pharmacogenomics work?
• Drugs interact with your body in numerous ways, depending both on how you take the drug and where the drug acts
in your body.
• After you take a drug, your body needs to break it down and get it to the intended area.
• Your DNA can affect multiple steps in this process to influence how you respond to the drug.
• Some examples of these interactions include
-Drug Receptors
-Drug Uptake
-Drug Breakdown
-Targeted Drug Development

27.
Drug Receptors. Some drugs need to attach to proteins on the surface of cells called receptors
in order to work properly. Your DNA determines what type of receptors you have and how
response to the drug. You might need a higher or lower amount of the drug than most people

28.
Drug receptors
• Receptor is a macromolecule in the membrane or inside the cell that specifically (chemically) bind a
ligand (drug).
• The binding of a drug to receptor depends on types of chemical bounds that can be established
between drug and receptor.
• The strength of this chemical bonds (covalent, ionic, hydrogen, hydrophobic) determine the degree
of affinity of ligand to receptor.
• Ligands (drugs) that attracted the receptors may be classified as agonists or antagonists.
• An agonist is a drug that binds to the receptor, producing a similar response to the intended
chemical and receptor. Whereas an antagonist is a drug that binds to the receptor either on
the primary site, or on another site, which all together stops the receptor from producing a
response.
• Agonists produce the biological response as a results of receptor –ligand interactions therefore
agonists posses efficacy.
• On the contrary antagonists did not provoke any biological activity after binding to its receptor.

29.
•Example: Breast Cancer and T-DM1
•Some breast cancers make too much HER2, a receptor, and this extra HER2 helps the cancer
•The drug T-DM1 can be used to treat this type of breast cancer and works by attaching to
killing them.
• If you have breast cancer, your doctor may test a sample of your tumor to determine if T-
• If your tumor has a high amount of HER2 (HER2 positive), your doctor may prescribe T-DM1.
•If your tumor does not have enough HER2 (HER2 negative), T-DM1 will not work for you.

30.
What is T-DM1 breast cancer treatment?
• T-DM1 contains a monoclonal antibody called trastuzumab that binds to a protein called
HER2, which is found on some breast cancer cells.
• It also contains an anticancer drug called DM1, which may help kill cancer cells.
• T-DM1 is a type of antibody-drug conjugate. Also called ado-trastuzumab emtansine
and Kadcyla.

31.
Drug Uptake. Some drugs need to be actively taken into the tissues and cells in which they act.
Your DNA can affect uptake of certain drugs. Decreased uptake can mean that the drug does
to build up in other parts of your body, which can cause problems. Your DNA can also affect
removed from the cells in which they act. If drugs are removed from the cell too quickly, they

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• Example: Statins and Muscle Problems.
• Statins are a type of drug that act in the liver to help lower cholesterol.
• In order for statins to work correctly, they must first be taken into the liver.
• Statins are transported into the liver by a protein made by the SLCO1B1 gene.
• Some people have a specific change in this gene that causes less of a statin called simvastatin
to be taken into the liver.
• When taken at high doses, simvastatin can build up in the blood, causing muscle problems,
including weakness and pain.
• Before prescribing simvastatin, your doctor may recommend genetic testing for
the SLCO1B1 gene to check if simvastatin is the best statin for you or to determine what dose
would work best.

33.
Drug Breakdown. Your DNA can affect how quickly your body breaks down a drug. If you
break the drug down more quickly than most people, your body gets rid of the drug faster
drug or a different drug. If your body breaks the drug down more slowly, you might need less

34.
Example: Depression and Amitriptyline.
• The breakdown of the antidepressant drug amitriptyline is influenced by two genes
called CYP2D6 and CYP2C19.
• If your doctor prescribes amitriptyline, he or she might recommend genetic testing for
the CYP2D6 and CYP2C19 genes to help decide what dose of the drug you need.
• If you breakdown amitriptyline too fast, you will need a higher dose for it to work, or you
may need to use a different drug.
• If you breakdown amitriptyline very slowly, you will need to take a smaller dose or will
need to take a different drug to avoid a bad reaction

35.
Targeted Drug Development.
• Pharmacogenomic approaches to drug development target the underlying problem
symptoms.
• Some diseases are caused by specific changes (mutations) in a gene.
• The same gene can have different types of mutations, which have different effects.
• Some mutations may result in a protein that does not work correctly, while others
made at all.
• Drugs can be created based on how the mutation affects the protein, and these drugs
type of mutation.

36.
•Example: Cystic Fibrosis and Ivacaftor
•Cystic fibrosis is caused by mutations in the CFTR gene which affect the CFTR protein.
•The CFTR protein forms a channel, which acts as a passageway to move particles across
the cells in your body.
•For most people the protein is made correctly, and the channel can open and close.
• Some mutations that cause cystic fibrosis result in a channel that is closed.
•The drug ivacaftor acts on this type of mutation by forcing the channel open.
•Ivacaftor would not be expected to work for people with cystic fibrosis whose mutations
cause the channel not to be made at all.

37.
Example: Cystic Fibrosis

38.
Genetic Drug Response Profiles
• Rapid sequencing and single nucleotide polymorphisms (SNPs) will play a major role in
associating sequence variations with heritable clinical phenotypes of drug or xenobiotic
response.
• SNPs occur approximately once every 300–3,000 base pairs if one compares the
genomes of two unrelated individuals.
• Any two individuals thus differ by approximately 1–10 million base pairs, i.e., in < 1% of
the approximately 3.2 billion base pairs of the haploid genome (23 chromosomes).
• Pharmacogenomics focuses on SNPs for the simple and practical reason that they are
both the most common and the most technically accessible class of genetic variants.

39.
Single nucleotide polymorphism (SNP)
• There are positions in a genome where some individuals have one nucleotide (e.g. a G ) and otherhs have a
different nucleotide (e.g. a C)
• Polymorphism – “ poly ” many “morphe “ form

40.
• Genetic variability of drug metabolizing enzymes and drug transporters has been associated with
interindividual differences in pharmacokinetics and pharmacodynamics.
• Such differences may result in variation in drug efficacy, safety and treatment outcomes in a
number of frequently prescribed drugs.
• Variation in the response to equivalent drug concentrations arises because of various factors, such
as differences in receptor number and structure, receptor-coupling mechanisms and
physiological changes in target organs resulting from differences in genetics, age and health
• Drug response can be impacted by several factors including diet, comorbidities, age, weight,
drug–drug interactions, and genetics.

41.
• For clinical correlation studies in relatively small populations SNPs that occur at
frequencies of greater than 10% are most likely to be useful, but rare SNPs with a strong
selection component and a more marked effect on phenotype are equally important.
• Once a large number of these SNPs and their frequencies in different populations are
known, they can be used to correlate an individual’s genetic “fingerprint” with the
probable individual drug response.
• High-density maps of SNPs in the human genome may allow to use these SNPs as
markers of xenobiotic responses even if the target remains unknown, providing a “drug
response profile” associated with contributions from multiple genes to a response
phenotype (http://snp.cshl.org).

42.
• The ability to predict inter-individual differences in drug efficacy or toxicity will thus be
a realistic scenario for the future.
• Indeed, there is a rapidly growing effort to identify SNPs that will be useful for
identifying patients who are at high risk to experience adverse drug reactions or to
determine the best therapeutic approach in this particular patient.
• Thus, genotyping procedures will play an important role in future therapies.
• However, phenotyping methods will remain important to assess the clinical relevance
of genetic variations.

43.
The Effect of Drugs on Gene Expression
• Genomic technologies also include methods to study the expression of large groups of
genes and indeed the entire products (mRNAs) of a genome.
• Most drug actions produce changes in gene expression in individual cells or organs.
• This provides a new perspective for the way in which drugs interact with the organism and
provide a measure of the drug’s biological effects.
• For instance, numerous drugs induce their own metabolism and the metabolism of other
drugs by interacting with nuclear receptors such as AhR, PPAR, PXR and CAR.
• This phenomenon has major clinical consequences such as altered kinetics, drug-drug
interaction or changes in hormone and carcinogen metabolism.

44.
What is gene expression?
• Gene expression is the process by which the instructions in our DNA are converted into a
functional product, such as a protein.
• When the information stored in our DNA is converted into instructions for making proteins or other
molecules, it is called gene expression.
• Gene expression is a tightly regulated process that allows a cell to respond to its changing
environment.
• It acts as both an on/off switch to control when proteins are made and also a volume control that
increases or decreases the amount of proteins made.
• There are two key steps involved in making a protein, transcription and translation.

45.
•Transcription is when the DNA in a gene is copied to produce an RNA transcript
called messenger RNA (mRNA).
•This is carried out by an enzyme? called RNA polymerase which uses available bases
from the nucleus of the cell to form the mRNA.
•RNA is a chemical similar in structure and properties to DNA, but it only has a single
strand of bases and instead of the base thymine? (T), RNA has a base called uracil (U).
Transcription

46.
•Translation occurs after the messenger RNA (mRNA) has carried the transcribed
‘message’ from the DNA to protein-making factories in the cell, called ribosomes.
•The message carried by the mRNA is read by a carrier molecule called transfer
RNA (tRNA).
•The mRNA is read three letters (a codon) at a time.
•Each codon specifies a particular amino acid. For example, the three bases ‘GGU’ code
for an amino acid called glycine.
•As there are only 20 amino acids but 64 potential combinations of codon, more than one
codon can code for the same amino acid. For example, the codons ‘GGU’ and ‘GGC’ both
code for glycine.
Translation

47.
•Each amino acid is attached specifically to its own tRNA molecule.
•When the mRNA sequence is read, each tRNA molecule delivers its amino acid to the
ribosome and binds temporarily to the corresponding codon on the mRNA molecule.
•Once the tRNA is bound, it releases its amino acid and the adjacent amino acids all join
together into a long chain called a polypeptide.
•This process continues until a protein is formed.
•Proteins carry out most of the active functions of a cell

48.
• Genomics is providing the technology to better analyze these complex multifactorial
situations and to obtain individual genotypic and gene expression information to
assess the relative contributions of environmental and genetic factors to variation.
Interaction of genes and drugs

49.
Pharmacogenomics in Drug Discovery and Drug
Development
• The identification of all genes, and the studies of ultimately all protein variants
expressed in cells and tissues that cause, contribute to or modify a disease will lead to
new “drugable” and “non-drugable” targets, prognostic markers of disease states or
severity of disease information.
• The pharmaceutical industry obviously has realized this potential, and chapter 6 in
discuss this particular aspects of pharmacogenomics.
• Pharmacogenomic approaches and technologies for drug discovery and drug
development have recently been reviewed
• It is obvious that the discovery of genes and proteins involved in the pathogenesis of
disease allows the definition of new drug targets and promises to profoundly change
the field of medicine in the future.