Pharmacogenomics A promise of personalised drugs

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PharmacogenomicsA promise of personalised
drugs

• A great many people suffer from adverse drug
  reactions which can be so severe that it results
  in death. These reactions are due to either an
  over or under expression of an enzyme that
  metabolises the drug
• Enzymes are proteins, and proteins are coded in
  your DNA, this means that the problem of adverse
  drug reactions can be linked to errors in DNA
• This is the premise of Pharmacogenomics

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• In pharmacogenomics, the prescription of a drug
  is based on checking the individuals for genomic
  errors that would not allow for correct
  metabolism of the drug
• The individuals DNA is sequenced (see box 1) and
  SNPs (see box 2) are located and
  identified
• From this, a fairly certain assumption can be
  made as to whether the drug being prescribed to
  the patient would cause any kind of adverse drug
  reaction
• This is very useful for the prescription of one
  particular drug from a range of available ones,
  based on reactivity to the patient as well as
  efficacy

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What is a SNP?
Box 2

• Single Nucleotide Polymorphisms or SNPs as they
  are known, form the basis for pharmacogenomics.
• They are single nucleotide changes or variation
  in genome of different individuals
• Most are located on the outside of the coding
  regions of the individuals DNA
• The SNPs that are of importance are those that
  are found within the exons the regions for gene
  coding
• They may predispose individuals to certain
  diseases and may interfere with the metabolism of
  some drugs
• SNPs are not responsible for disease but are
  rather a marker or indicator of disease
• Databases of SNPs have been produced and these
  are used to compare against a patient, to see if
  they share these anomalies(1)
• The SNP databases are formed by comparing genomes
  of people with a known reaction or disease
  against someone who does not and the differences
  quantified

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DNA Sequencing
Box 1

• The crux of all pharmacogenomic research is the
  sequencing of DNA, to search for markers. There
  are many different ways of doing this
• FACS
• (Fluorescence-activated chromosome sorting)
• (see box 3)
• DNA microarrays (see box 4)

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FACS(Fluorescence-activated chromosome sorting)
Box 3

• Chromosomes at the metaphase stage of the cell
  cycle are stained with two kinds of fluorescent
  dye, one that stains AT rich regions and another
  that stains GC rich regions
• The chromosomes are removed from the cell and
  suspended in a solution
• This solution is sprayed out a nozzle that
  regulates one chromosome per droplet of
  suspension
• It is sprayed through laser beam which causes the
  dyes to fluoresce
• Each chromosome has its own fluorescent
  signature, which is read electronically
• According to the signature, the droplets
  containing the chromosomes, are sorted into
  different collecting tubes
• This is a useful technique because it saves time
  by isolating the chromosome which contains the
  gene of interest

http//www.ncbi.nlm.nih.gov/books/bv.fcgi?ridiga.
section.1151
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A graphical representation of the principle
behind FACS
Picture from http//www.ncbi.nlm.nih.gov/books/bv.
fcgi?ridiga.figgrp.1157
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DNA microarrays

• Are essentially glass chips with thousands of
  cDNA probes anchored to them
• The mRNA from the target cell is converted into
  cDNA by reverse transcriptase, and labeled with a
  fluorescent marker
• This is allowed to hybridize with the microarray
• If the sequence is complementary to the probe, it
  will fluoresce

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Fact

• Adverse drug reaction are one of the leading
  causes of hospitalization and death in the USA.
  The need for pharmacogenomics can therefore not
  be over emphasized (www.ncbi.com)

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Bibliography

• (1) McCarthy J J Hilfiker R (2000) The use of
  single nucleotide polymorphism maps in
  pharmacogenomics. Nature Biotechnology 18
  505-508
• http//www.ncbi.nlm.nih.gov/books/bv.fcgi?ridiga.
  figgrp.1157
• www.esainc.com/img/pics/dna.jpg
• http//www.ncbi.nlm.nih.gov/books/bv.fcgi?ridiga.
  section.1151