Pharmaceutical

Biotechnology

[PHARMAGENOMICS]
Khushpreet Singh
7050014

Genetic markers such as single-nucleotide polymorphisms may lead to

personalized medicines for a wide variety of diseases
Pharmacogenomics
What if when you went to the doctor's office, instead of making an
educated guess about what medication to prescribe, your doctor gave you
a genetic test that indicated which medication was right for you? Such a
test might predict how you would respond to a drug or determine whether
you were in a group of patients who would suffer severe side effects.
Sound outlandish? It's not all that far away, and pharmacogenetics, often
called pharmacogenomics, is the field that will make it happen.

As the name suggests, pharmacogenetics is the intersection of the fields of pharmacology and
genetics. Simply stated, pharmacogenetics is the study of how genetic variations affect the
ways in which people respond to drugs. These variations can manifest themselves as
differences in the drug targets or as differences in the enzymes that metabolize drugs. A
difference in the target will usually lead to differences in how well the drug works, whereas
differences in metabolizing enzymes can result in differences in either efficacy or toxicity. It's
also possible that genes not directly involved in a particular pathway could end up being
predictive of clinical outcomes.

Although pharmacogenomics has the potential to radically change the way health care is
provided, it is only in its infancy. In the future, pharmacogenomics could find uses along the
entire drug discovery and development timeline, all the way from target discovery and
validation to late-stage clinical trials. Beyond that, pharmacogenomic tests could find their
way into the doctor's office as a means to get the right medicine to the right patient at the
right time.

While genetics and genomics are often used synonymously, pharmacogenetics is more
focused in scope than and is viewed as a subset of pharmacogenomics, which encompasses
factors beyond those that are inherited.

Some people believe that pharmacogenomics will lead to the stratification of diseases into
genetically defined categories.

MULTIPLE GENOMES Just looking at a group of people is proof that there isn't just one
human genome. Identifying SNPs requires looking for differences in DNA sequences across
an ethnically diverse panel of individuals.

Pharmacogenomics will lead to the stratification of diseases into

genetically defined categories.

For pharmacogenetics to be effective, markers must be found that indicate the connection
between drug response and genetic makeup. The markers that companies are pursuing most
diligently are known as single-nucleotide polymorphisms, or SNPs (pronounced "snips").
SNPs, which are defined only in relation to a population, are variations in DNA at a single
base that are found in at least 1% of the population.
A group called the SNP Consortium--a partnership of pharmaceutical and technology
companies, academic research centers, and the Wellcome Trust--is working to publish a high-
density SNP map of the human genome. Although the consortium's original goal was to map
300,000 SNPs, it already has a publicly available map of more than a million SNPs. The SNP
database, which is maintained by Cold Spring Harbor Laboratory, can be accessed at
http://snp.cshl.org/db/snp/map.

FAMILY TREE Identifying genetic causes for common diseases requires the use of a large
group of distantly related individuals. Here, deCODE Genetics uses the Icelandic genealogy to
determine how a group of asthma patients are related going back 11 generations.
So, Pharmacogenomics is the study of the genetic factors that determine how a person will
respond to a drug. The term comes from the words "pharmacology" and "genomics," and is
therefore the cross-roads of pharmaceuticals and genetics. It is a rapidly growing field in
human genetics.

Scientists think that the same genetic differences that make each person unique (such as
appearance, behavior) may also be the same factors that determine whether or not a drug will
work against our diseases and whether it will produce side effects. The aim of
pharmacogenomics is to tailor the treatment to the patient. Pharmacogenomics is opening the
doors to assessing a person's genetic background, and using that information to make
informed treatment decisions, including the odds that the treatment will be effective from the
start.

Pharmacogenomics is expected to bring many benefits to patients and the health care
industry, increase the number of new drugs and reduce the costs associated with drug
development.

Pharmacogenomics today
Currently, most of the research done in pharmacogenomics studies is on the cytochrome P450
(CYP) family of liver enzymes. This is because CYP enzymes are responsible for breaking
down more than 30 different classes of drugs. DNA variation in genes that code for these
enzymes can affect their ability to break down certain drugs. Clinical trials researchers use
genetic tests for variations in cytochrome P450 genes to screen and monitor patients. Less
active or inactive forms of CYP enzymes that cannot break down and eliminate drugs from
the body can cause overdoses in patients.

Two theoretical models

Scientists are focusing on mapping out the genomic differences between different phenotype-
expressing groups. This is the central focus of both the genotype-to-phenotype (G2P) and the
phenotype-to-genotype (P2G) approaches. These are the two theoretical models being used in
pharmacogenomics today - genotype being human genetic variation (a man has an XY
chromosome and a woman has an XX chromosome, this is a genotypic variation), and
phenotype being human individual/ group variation (one is male and the other is female) .

G2P
The G2P approach consists of tracking down sets of genes that are thought to be important in
regulating the response to drugs. Variation in the DNA sequences of those genes is then
catalogued so that the different phenotypes associated with this variation can be identified.
This approach is beneficial when studying effects whose molecular mechanisms are well
understood. For example, the G2P approach is useful for studying gene families known to be
important for pharmacokinetics - the study of how drugs are absorbed, distributed and cleared
from the body. G2P is also recognized as useful to pharmacodynamics - the study of how
drugs achieve their therapeutic effect.
P2G
The P2G approach is the reverse. It consists of tracking down phenotypic variations in drug
responses. This leads to the identification of genes that could explain these variations. The
genotypic variation is then compared to the phenotypic variation, so that its clinical
usefulness can be confirmed. The P2G approach is sometimes considered advantageous when
studying pharmacogenomic effects whose significant phenotypical variations to drug
response can be easily observed and measured.

Genotyping technology
The mapping out of genotype-phenotype interactions is done mainly through single
nucleotide polymorphism genotyping. Single nucleotide polymorphisms (SNPs - pronounced
"snips") are naturally occurring variations of single nucleotides at set positions in a
population's genome. For SNPs to be used to predict a person's drug response, a person's
DNA must be examined (sequenced) for the presence of specific SNPs. The human genome
is made up of strings of nucleotides that can be:

A - adenine,
C - cytosine,
T - thymine, or
G - guamine.

As an example, at a SNP location, 70% of all human chromosomes may have an A at a

certain location, while the remaining 30% have a G. This genotypic difference can cause a
phenotypic difference in hair colour, height, or drug response, depending on the gene.

Detection of differences can also be done through haplotype characterization (the

characterization of SNPs that are usually genetically linked and transmitted together). This
characterization is considered better in detecting polygenic associations, but the process is
more complex and costs more than SNP characterization.

SNPs have certain technical properties that make detection of gene variations possible
through numerous high-throughput (see below) approaches. Also, the great amount of
sequence information from the Human Genotype Project has enabled organizations to look
for SNP variation in the human population. The SNP Consortium, a group of pharmaceutical
and technological companies, academic institutions and a medical research charity, has
identified and mapped 300,000 SNPs and provides information on almost 900,000 mapped
SNPs in the human genome.

Traditional gene sequencing technology is very slow and expensive. This has been a barrier
to the widespread use of SNPs as a diagnostic tool. DNA microarrays (or DNA chips) are an
evolving technology that may make it possible for doctors to examine their patients for
specific SNPs quickly and affordably. A single microarray can now be used to screen
100,000 SNPs found in a patient's genome in a few hours. As DNA microarray technology
evolves, SNP screening in the doctor's office to determine a patient's response to a drug -
before a drug is prescribed - will likely become common.
Measuring techniques
Several techniques have been developed to measure the genotypes of SNPs, called high-
throughput (HT) genotyping technology. A common feature of HT genotyping is the use of
the polymerase chain reaction (PCR). PCR is a laboratory method used to make many copies
of a DNA fragment in minutes using an enzyme called polymerase.

Some other potential benefits and barriers

In addition to developing more accurate methods of determining the proper drug dosages,
pharmacogenomics is expected to contribute to advanced screening for disease. Knowing
your genetic code will let you to make lifestyle and environmental changes at an early age so
you can avoid or lessen the severity of a genetic disease. Better vaccines made of genetic
material - either DNA or RNA - are also expected to activate the immune system but will not
be able to cause infections.

The complexity of finding gene variations that affect drug response may slow progress in
pharmacogenomics. Because SNPs occur every 100 to 300 bases along the three-billion-base
human genome, millions of SNPs need to be identified and analyzed to determine any
involvement in drug response. We also have limited knowledge of which genes are involved
in each drug response.

Looking at the social-ethical aspects

The issues of large-scale genotyping of populations, which the wider use of
pharmacogenomics-based drug discovery and medicine will require, are complex. They also
affect all of society, not just the pharmaceutical industry, regulatory bodies and patients.
Scientists, industry and academia have analyzed and discussed many of these issues. Their
views currently form the basis for the start of discussion covering the wider ethical, political,
social and technological aspects of the use of pharmacogenomics.

Pharmacogenomics in the future

Pharmacogenomics is not yet a major field of study in Canada. However, the need to reduce
adverse drug reactions and costs for the health care system may encourage pharmacogenomic
research programs by both private enterprises and government. The reduction of drug
development time and the need to get more new drugs on the market are also making
pharmaceutical companies increase pharmacogenomics use in their clinical research
programs.