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Pharmacogenetics:
Everyone’s just a little different!
Alan P. Agins, Ph.D.
President, PRN AssociatesContinuing Medical Education, Tucson, AZ
“If it were not for the great variability among individuals,medicinemight as well be a science and not an art.” 
SirWilliam Osler, 1892Relatively newfieldof study withinthe realm ofpharmacologyPatientscan responddifferentlytoagiventherapeuticagenteveniftheyhavethesameillness.The samedoseofa givendruginsomepatientscausesverydifferentplasmalevelsanddifferenttherapeuticresponsethat cannot beexplained by weight, age or gender
Pharmacogenetics:Pharmacogenetics
The study of genetically determinedinterindividual differences intherapeutic response to drugs andsusceptibility to adverse effects
Pharmacogenomics:
Use of genome based techniques indrug development
Thedifferencesintheresponsetoagivendrugcanbe due to twomajorpharmacological factorsthatcan varywithgeneticinfluence:
 – 
Pharmacokinetic:
Geneticallybaseddifferencesintheprocessesinfluencingbioavailability
Absorption, distribution, metabolism,elimination – 
Pharmacodynamic:
Geneticallybaseddifferencesinthetargetsatwhichthedrugacts
Receptors, enzymes, ion channels, etc
Pharmacogenetics
Polymorphisms
DrugmetabolismADRsToxicityDiseasesusceptibilityReceptorsensitivityDrugtransportTherapeuticEfficacy
Consequences of Polymorphisms
 
2
Polymorphism
Geneticvariationoccuringwitha frequencyof1% ormore inthepopulation
1
. SNP
(singlenucleotidepolymorphism):2.
Insertion/deletion polymorphism
: insertionor deletion of a few nucleotides3.
Variable number tandem repeats
: variationin the number of times a sequence of severalhundred base pairs is repeated4.
Simple tandem repeats
: 2-4 nucleotidesrepeated a variable number of times
Polymorphism vs. Mutation
Polymorphism is defined as a variationin more than 1% of the population.Mutations are rare differences whichoccur in less than 1% of the population(usually much less than 1%).It is estimated that about 10 millionSNPs exist in human populationsMost of these SNPs are neutral
Single Nucleotide Polymorphism
•Most frequent type•Difference in a singlebase of the genomicsequence•Usually 1/1000 bases•Most do not influencethe structure orfunction of proteins
SNPscan occur
In Exons
 – 
may alter the structure of proteins andmay lead to functional consequences
In Introns
 – 
may influence splicing
In Regulatory regions
 – 
may influence expression of the gene
 
Genotype
:genestructureencodingforthegivencharacteristics
Phenotype
: themanifestationofthegenotype, whichcanbe observedandcanbe influencedbyotherfactors:
 – 
Othergeneproducts
 – 
Environment
 – 
AcquiredcharacteristicsFrequencyand functional relevance ofgeneticpolymorphismsdiffersgreatlyamongethnicgroups
Pharmacogenetics
Determinationofgenotype:
 – 
PCR, gene sequencing
Determinationofphenotype:
 – 
Generally “after-the-fact”
 – 
Afteradministrationofa drug
 – 
Measure pharmacokineticparameters(halflife,clearance, plasmalevels)
 – 
Or, after unusual response or toxicity
Distributionofphenotypesinthepopulation:
 – 
Multimodal(usuallybi-ortrimodal)distribution-indicatesdeterminationbyasinglegenehavingpolymorphicvariants
Pharmacogenetics
 
3
SNP Polymorphisms in metabolicpathways areusuallybi-ortrimodal=twoorthreephenotypes
 – 
Enhanced(extensive)metabolizer
High rate of metabolism –often resultinginlowplasmaconcentrationofthedrug
usuallyheteozygoteorhomozygotedominant – 
Intermediatemetabolizer
 – 
Poormetabolizerornon-metabolizer:
Sloworno metabolism ofthedrugresultinginhighplasmaconcentrationforanextendedtime
Usuallyhomozygoterecessive
Pharmacogenetics
Pharmacogenetics andPredicted vs Unpredicted ADRs
++++/-MorbidityRareCommonFrequency+ / -+++DosedependenceNoYesPredictabilityIdiosyncratic:
relatedtopharmacogenetics
Augmented:relatedtothetherapeuticeffect
PM
   F  r  e  q  u  e  n  c  y
Enzyme ActivityIM / EM
“Wild type” 
EM / UEM
Tri-Modal Distribution
•
Stop codons
•
Deletions
•
Missense SNPs
•
Splice defects
•
Geneduplication
PharmacogeneticsofDrugMetabolism
Drugmetabolismis crucialindeterminingtherapeuticandadverseeffectsGeneticfactorsplayanimportantroleinindividualdifferencesofdrugmetabolism – 
PhaseI
Oxidation, reduction, hydroxilation,dealkylation, etc.
CytochromeP450 enzymesingut andliver
 – 
PhaseII
Conjugationwithglucuronicacid,glutathione, sulfate, acetate, etc
Aim: toincreasewatersolubility
Ususallyinthecytosol
CYP2C9CYP2C9CYP2C9CYP2D6
Pharmacogenetics andCytochrome P450
Major P450 IsoformsCYP3A4 -CYP2D6 -PolymorphismCYP2C19 -PolymorphismCYP2C9 -PolymorphismCYP1A2CYP2E1
Cytochrome P450CYP2D6Polymorphism
Discoveredinthe1970sOneofthemost widelystudiedpolymorphismsindrugmetabolism2% oftotalliverCYP contentMore than 50 alleles,up to a 1000-fold variation in the populationTrimodal Distribution
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