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CZ5225 Methods in Computational Biology

Lecture 9: Pharmacogenetics and individualvariation of drug response


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OutlineIntroduction

Differential drug efficacyPeople react differently to drugs

Why does drug response vary?Potential causes of variability in drug effectsGenetic variation

PharmacogeneticsWhat is Pharmacogenetics?Pharmacogenetics VS. PharmacogenomicsGenetic variation and drug responseDeterminants of Drug Efficacy and ToxicityExamples

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Differential drug efficacy

Same symptoms,Same findings,Same disease? Same drug

Same dose

Different Effects

Different patients

At a recommended prescribed dosage

a drug is efficacious in most.

not efficacious in others.

harmful in a few.

Lack of efficacy

Unexpected side-effects

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Patient population withsame disease phenotype Patients with normal response

to drug therapy

Patients with non-response todrug therapy

Patients with drug toxicity

Genotyping

Toxic responders

Non-responders

Responders

People react differently to drugs

One size does not fit all

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Why does drug response vary?Genetic variationPrimarily two types of genetic mutation events create all

forms of variations:Single base mutation which substitutes one nucleotide for another

--Single nucleotide polymorphisms (SNPs)

Insertion or deletion of one or more nucleotide(s)

--Tandem Repeat Polymorphisms--Insertion/Deletion Polymorphisms

Polymorphism: A genetic variation that is observed at a frequency of >1% in a population

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Single nucleotide polymorphisms (SNPs)

SNPs are single base pair positions in genomic DNA at whichdifferent sequence alternatives (alleles) exist wherein the leastfrequent allele has an abundance of 1% or greater.

For example a SNP might change the DNA sequenceAAGCTTAC

to A T GCTTAC

SNPs are the most commonly occurring genetic differences.

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Tandem Repeat Polymorphisms

Tandem repeats or variable number of tandem repeats (VNTR)are a very common class of polymorphism, consisting of variablelength of sequence motifs that are repeated in tandem in a variable

copy number.

Based on the size of the tandem repeat units:Microsatellites or Short Tandem Repeat (STR)

repeat unit: 1-6 (dinucleotide repeat: CACACACACACA)Minisatellites

repeat unit: 14-100

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Insertion/Deletion Polymorphisms

Insertion/Deletion (INDEL) polymorphisms are quite common andwidely distributed throughout the human genome.

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Due to individual variation 20-40% of patients benefit from an approved drug

70-80% of drug candidates fail in clinical trials

Many approved drugs removed from the market due toadverse drug effects

The use of DNA sequence information to measure and

predict the reaction of individuals to drugs.Personalized drugs

Faster clinical trials

Less drug side effects Pharmacogenetics

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PharmacogeneticsStudy of i nter individual variation i n DNA sequence related todrug absorption and disposi tion (Pharmacokinetics) and/or drugaction (Pharmacodynamics) including polymorphic variation ingenes that encode the functions of transporters, metabolizingenzymes, receptor s and other proteins.

The study of how people respond di fferently to medicines due totheir genetic inher i tance is cal led pharmacogenetics.

Correlating heritable genetic variation to drug response

An ultimate goal of pharmacogenetics is to understand how someone'sgenetic make-up determines, how well a medicine works in his or herbody, as well as what side effects are likely to occur.

Right medicine for the right patient

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PharmacogeneticsThe study of variations in genes thatdetermine an individuals response todrug therapy.

Common variation in DNA sequence(i.e. in >1% of population)

Genetic Polymorphism:SNPs; INDEL; VNTRs

Potential Target Genes are those that encode:Drug-metabolizing enzymesTransportersDrug targets

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Pharmacologic effect

Clinical response

Toxicity Efficacy

DISTRIBUTION

ABSORPTION

ELIMINATION

Pharmacokinetics

Pharmacodynamics

dose administered

drug in tissues of distribution

concentration in systemic circulation

concentration at site of action

metabolism and/or excretion

Pharmacokinetic factors

- Absorption- Distribution- Metabolism- Elimination

Pharmacodynamic factors- Target proteins- Downstream messengers

Determinants of Drug Efficacy and ToxicityA patients response to a drug may depend on factors that can varyaccording to the alleles that an individual carries, including :

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Examples:EM phenotype: Extensive metabolizer; IM phenotype: intermediate metabolizer;PM phenotype: poor metabolizer; UM phenotype: ultrarapid metabolizers

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Any questions?

Thank you

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Genotype VS. Phenotype

The interaction between genotype and phenotype has often beendescribed using a simple equation:

genotype + environment phenotype A slightly more nuanced version of the equation is:

genotype + environment + random- variation phenotype

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