Biochemical Basis of Therapeutics
Pharmacogenetics
What is pharmacogenetics?
● Pharmacogenetics: a branch of pharmacy looking at the variation in genetic
sequences which impacts upon drug action
● Most populations tend to show a large inter-individual variability in drug response
and toxicity to all major classes of drugs given at a standard dose
● 15-30% of inter-individual differences in drug metabolism and response is due to
genetic factors
○ This can be up to 95% for some drugs
● Consensus sequence: where each nucleotide is in its most common position
○ The consensus sequence is derived from the Human Genome Project
■ The Human Genome Project ran from the 1990s to 2003, using a
variety of samples (ie ethnicity, age and sex)
● Chromosome maps are generated
● Large-scale DNA sequencing is undertaken
● Sequences are annotated
○ In 1999, the first chromosome (22) was sequenced
■ Those of non-African origin share 4% of DNA
with Homo neanderthalensis
■ Evidence shows that humans spread from
multiple geographical locations
■ 40 of our genes were obtained directly from
bacteria
■ 7% of protein families are vertebrate-specific
■ 40% of DNA is repetitive
■ 1.5-2% of DNA encodes for proteins
● Most DNA is made of regulatory
sequences
○ Wild-type (WT): the consensus sequence for a gene
■ Allele: a gene that has several versions which differ from the WT
● WT=*1 and mutated alleles= *2, *3…
● Ie CYP2C9*2 is predominantly found in Caucasians, and it
results in a reduction of warfarin metabolism so Rx doses must
be adjusted by a ⅓ less
How do SNPs arise?
● Single nucleotide polymorphisms (SNPs): the most common polymorphism (1.4
million), with one SNP every 300-1000bp depending on the sequence
○ SNPs define individuality, however, most are neutral and many cause disease
● Genetic mutation introduces new alleles into the gene pool and this occurs all the
time
1
, ○ The Earth is emitted ionising radiation from the Sun, but the atmosphere
protects against most of this (despite the hole in the ozone layer)
○ There is also radioactive decay in the mantle and core of the Earth which
results in a heating effect
■ Earth’s magnetic field (the geomagnetic field) deflects ionisation and
solar winds)
○ There is background radiation including radon leaks from the ground
How do alleles arise?
● Genetic mutation happens at a constant rate (the mutation rate)
○ The mutation rate can appear to slow down and increase (beneficial versus
detrimental)
● Mutations are likely to occur in non-coding regions due to the genome architecture
(this acts as a protective mechanism)
○ Mutations can occur in promoter regions or splice sites but sometimes they
occur in a coding sequence
■ Synonymous- there is no change in the amino acid, so no change in
protein function
● Synonymous mutations usually occur in the 3rd base of the
triple codon
● The allele is given a letter suffix where *1A is always the
wild-type allele and subsequent letters denote a mutation
■ Nonsynonymous- there is a change in the 1st base (or 2nd) of the
triple codon which changes the amino acid sequence, which can result
in three outcomes
● There may be no functional amino acid change (ie Glu to Asp
mutation)
● There may be a small change in protein function (ie Arg114Cys
in cytochrome P450 2C9)
● There may be a major change in protein function (ie Glu6Val in
haemoglobin S)
○ The impact of nonsynonymous mutation is dependent
on what is affected (is it the active site or the structural
part?)
■ Frameshift- the addition/deletion of a nucleotide base, which moves
the open reading frame
● The gene sequence may increase, making a longer protein
● A stop codon may be introduced leading to the synthesis of a
truncated protein
○ Either way, this nearly always produces an inactive
protein
■ Gene duplication- many copies of the same allele are repeated so too
much protein is made
● Ie Cytochrome P450 2D6*2 results in ultrarapid metabolism in
the individual, and CYP2D6 is responsible for the metabolism
and elimination of about 25% of clinically used drugs
2
Pharmacogenetics
What is pharmacogenetics?
● Pharmacogenetics: a branch of pharmacy looking at the variation in genetic
sequences which impacts upon drug action
● Most populations tend to show a large inter-individual variability in drug response
and toxicity to all major classes of drugs given at a standard dose
● 15-30% of inter-individual differences in drug metabolism and response is due to
genetic factors
○ This can be up to 95% for some drugs
● Consensus sequence: where each nucleotide is in its most common position
○ The consensus sequence is derived from the Human Genome Project
■ The Human Genome Project ran from the 1990s to 2003, using a
variety of samples (ie ethnicity, age and sex)
● Chromosome maps are generated
● Large-scale DNA sequencing is undertaken
● Sequences are annotated
○ In 1999, the first chromosome (22) was sequenced
■ Those of non-African origin share 4% of DNA
with Homo neanderthalensis
■ Evidence shows that humans spread from
multiple geographical locations
■ 40 of our genes were obtained directly from
bacteria
■ 7% of protein families are vertebrate-specific
■ 40% of DNA is repetitive
■ 1.5-2% of DNA encodes for proteins
● Most DNA is made of regulatory
sequences
○ Wild-type (WT): the consensus sequence for a gene
■ Allele: a gene that has several versions which differ from the WT
● WT=*1 and mutated alleles= *2, *3…
● Ie CYP2C9*2 is predominantly found in Caucasians, and it
results in a reduction of warfarin metabolism so Rx doses must
be adjusted by a ⅓ less
How do SNPs arise?
● Single nucleotide polymorphisms (SNPs): the most common polymorphism (1.4
million), with one SNP every 300-1000bp depending on the sequence
○ SNPs define individuality, however, most are neutral and many cause disease
● Genetic mutation introduces new alleles into the gene pool and this occurs all the
time
1
, ○ The Earth is emitted ionising radiation from the Sun, but the atmosphere
protects against most of this (despite the hole in the ozone layer)
○ There is also radioactive decay in the mantle and core of the Earth which
results in a heating effect
■ Earth’s magnetic field (the geomagnetic field) deflects ionisation and
solar winds)
○ There is background radiation including radon leaks from the ground
How do alleles arise?
● Genetic mutation happens at a constant rate (the mutation rate)
○ The mutation rate can appear to slow down and increase (beneficial versus
detrimental)
● Mutations are likely to occur in non-coding regions due to the genome architecture
(this acts as a protective mechanism)
○ Mutations can occur in promoter regions or splice sites but sometimes they
occur in a coding sequence
■ Synonymous- there is no change in the amino acid, so no change in
protein function
● Synonymous mutations usually occur in the 3rd base of the
triple codon
● The allele is given a letter suffix where *1A is always the
wild-type allele and subsequent letters denote a mutation
■ Nonsynonymous- there is a change in the 1st base (or 2nd) of the
triple codon which changes the amino acid sequence, which can result
in three outcomes
● There may be no functional amino acid change (ie Glu to Asp
mutation)
● There may be a small change in protein function (ie Arg114Cys
in cytochrome P450 2C9)
● There may be a major change in protein function (ie Glu6Val in
haemoglobin S)
○ The impact of nonsynonymous mutation is dependent
on what is affected (is it the active site or the structural
part?)
■ Frameshift- the addition/deletion of a nucleotide base, which moves
the open reading frame
● The gene sequence may increase, making a longer protein
● A stop codon may be introduced leading to the synthesis of a
truncated protein
○ Either way, this nearly always produces an inactive
protein
■ Gene duplication- many copies of the same allele are repeated so too
much protein is made
● Ie Cytochrome P450 2D6*2 results in ultrarapid metabolism in
the individual, and CYP2D6 is responsible for the metabolism
and elimination of about 25% of clinically used drugs
2
