FARMACOGENETICA:verso la personalizzazione

della terapia

Siena, 28/02/2011

dopo l’infarto del miocardio,i tumori e l’ictus

dopo l’infarto del miocardio,i tumori e l’ictus

Le reazioni avverse ai farmaciLe reazioni avverse ai farmaci

(ADR=ADVERSE DRUGREACTION)

(ADR=ADVERSE DRUGREACTION)

costituiscono la quarta causadi morte negli Usa

costituiscono la quarta causadi morte negli Usa

La maggior parte di questeimprevedibili morti è dovutaa variabilità individuale nelle

risposte ai farmaci

La maggior parte di questeimprevedibili morti è dovutaa variabilità individuale nelle

risposte ai farmaci

L’aspetto speculare di questavariabilità è la mancata efficacia

di un determinato trattamentofarmacologico con esposizione

del paziente ai soli effetti collateralio tossici del trattamento stesso

senza alcun beneficioterapeutico

senza alcun beneficioterapeutico

La variabilità individualenelle risposte ai farmaciha basi genetiche

La variabilità individualenelle risposte ai farmaciha basi genetiche

risiede in differenze di sequenzaesistenti a carico dei genicodificanti per le proteinecoinvolte nella rispostaad un determinato trattamentofarmacologico

risiede in differenze di sequenzaesistenti a carico dei genicodificanti per le proteinecoinvolte nella rispostaad un determinato trattamentofarmacologico

Che cosa è laFarmacogenetica?

La FARMACOGENETICAè la disciplina che studia le

basi genetichedella risposta individuale

ai farmaci

I geni che influenzano la rispostaad un determinato trattamentofarmacologico possono essere

distinti in due grandi classi

I geni che influenzano la rispostaad un determinato trattamentofarmacologico possono essere

distinti in due grandi classi

22

Geni codificanti per il bersaglioterapeutico primario, comeper esempio recettori o enzimi

Geni codificanti per il bersaglioterapeutico primario, comeper esempio recettori o enzimi

Geni codificanti per proteinecoinvolte nell’assorbimento,metabolismo ed escrezionedel farmaco

Geni codificanti per proteinecoinvolte nell’assorbimento,metabolismo ed escrezionedel farmaco

I geni che influenzano la rispostaai farmaci possono presentare

varianti alleliche nella popolazione,cioè, in altri termini, essere

polimorfici

I geni che influenzano la rispostaai farmaci possono presentare

varianti alleliche nella popolazione,cioè, in altri termini, essere

polimorfici

Tali polimorfismi sono spessoa carico di singole basi e vengono

pertanto definiti SNP

Single NucleotidePolymorphisms

Single NucleotidePolymorphisms

Si definiscono polimorficitutti quegli alleli (o loci)

che sono presenti almenonell’1% della popolazione

Si definiscono polimorficitutti quegli alleli (o loci)

che sono presenti almenonell’1% della popolazione

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TRASCRIZIONE

SPLICING

TRADUZIONE

Gli SNPs

vengono classificati

in 3 distinte categorie

SNP delle regioni codificanti(cSNP).SNP delle regioni codificanti(cSNP).

SNP perigenici (pSNP) cheinteressano le regioniregolatorie al 5’, le regionispecificanti i 5’ e 3’ non tradottidel mRNA, gli introni.

SNP perigenici (pSNP) cheinteressano le regioniregolatorie al 5’, le regionispecificanti i 5’ e 3’ non tradottidel mRNA, gli introni.

SNP che si trovano random(rSNP) nelle regioniintergeniche.

cSNPs

POLIMORFISMI A SINGOLONUCLEOTIDE

DELLE REGIONI CODIFICANTI

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pSNPs

POLIMORFISMI A SINGOLONUCLEOTIDE

DELLE REGIONI PERIGENICHE

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X

Si ritiene che in media vi siano 4 cSNPper gene; se si assume che nel genomaumano vi siano 35.000 geni, si stima chevi possano essere tra i 120.000 ei 200.000 cSNP che, con altri appropriaticalcoli, si traducono nel fatto che unindividuo-tipo è eterozigote per circa30.000 aminoacidi

Polymorphism II

2. Insertion/deletion polymorphism: insertion ordeletion of a few nucleotides

3. Variable number tandem repeats: a sequence ofseveral hundred base pairs is repeated (variation inthe number of times)

4. Simple tandem repeats (microsatellites): 2-4nucleotides repeated a variable number of times

Polimorfismi in enzimiresponsabili

del metabolismo dei farmaci

• Nomenclature of CYP genes:– Arabic number for gene family– Capital letter for gene subfamily– Arabic number for individual gene

• CYP enzymes of different gene families have a 40% or morehomology in their amino acid sequences, but enzymes withinone subfamily may have different substrates, regulation, etc.

• Over 70 % of total CYP content of the human liver is shared byseven subfamilies: CYP1A2, CYP2A6, CYP2B6, CYP2C,CYP2D6, CYP2E1, CYP3A

• Extent of metabolism is determined by– Affinity of substrate-enzyme complex– Relative abundance of a given CYP enzyme relative to the

total CYP content

Schema dei principalimeccanismi molecolari

che possono causareun alterato metabolismo

dei farmaci nell’uomo

• In relation to the capability to metabolise a drug thesubjects can be divide in three phenotypes

– Enhanced/extensive metaboliser:• intensive metabolisation, resulting in low plasma

concentration of the drug• usually heteozygote or homozygote dominant

– Intermedier metaboliser– Poor metaboliser or non metaboliser:

• Slow or no metabolisation of the drug resulting in highplasma concentration for an extended time

• Usually homozygote recessive

Effetti dei polimorfismidel citocromo P450

nel trattamentofarmacologico di

“poor metabolizers”

Effetti dei polimorfismidel citocromo P450

nel trattamentofarmacologico di

“poor metabolizers”

PolymorphicenzymePolymorphicenzyme

DecreasedclearanceDecreasedclearance

Adverseeffects

Adverseeffects

Reducedprodrug

activation

Reducedprodrug

activation

CYP2C9CYP2C9 S-WarfarinS-Warfarin BleedingBleeding LosartanLosartan

PhenytoinPhenytoin AtaxiaAtaxia

LosartanLosartan

TolbutamideTolbutamide HypoglycaemiaHypoglycaemia

NSAIDsNSAIDs GI-bleeding(?)GI-bleeding(?)

CYP2C19CYP2C19 OmeprazoleOmeprazole ProguanilProguanil

DiazepamDiazepam SedationSedation

Frequenza di individuiportatori di alleli

con copie multipledel citocromo P450

CYP2D6

Frequenza di individuiportatori di alleli

con copie multipledel citocromo P450

CYP2D6

PolymorphicenzymePolymorphicenzyme

DecreasedclearanceDecreasedclearance

Adverseeffects

Adverseeffects

Reducedprodrug

activation

Reducedprodrug

activation

CYP2D6CYP2D6 TricyclicTricyclic CardiotoxicityCardiotoxicity TramadolTramadol

Antidepres.Antidepres.

HaloperidolHaloperidol

PerphenazinePerphenazine

PerhexilinePerhexiline NeuropathyNeuropathy

SSRIsSSRIs

TolterodineTolterodine

CodeineCodeine

ParkinsonismParkinsonism

NauseaNausea

Ethylmor.Ethylmor.

CYP2D6• Discovered in the 1970s, one of the most widely studied

polymorphisms in drug metabolism• 2% of total liver CYP content• Distribuiton of PM: 7% of Caucasians, 1% of Asians• Involved in metabolism of several drugs

– Psychotropic medications: tricyclic antidepressants, SSRIs,classical and atypical antipsychotics

– Cardiovascular drugs– -receptor antagonists: metoprolol, propranolol, timolol– Phenacetine– D-penicillamine– Codeine– Abused drugs

Distribution of CYP2D6 enzymes indifferent populations

VariantVariantallelesalleles

EnzymeEnzymefunctionfunction

Allele frequency %Allele frequency %

CaucasiansCaucasians AsiansAsians BlackBlackAfricansAfricans

EthiopiansEthiopiansand Saudiand SaudiArabiansArabians

CYP2D6*2xNCYP2D6*2xN IncreasedIncreased 11--55 00--22 22 1010--1616

CYP2D6*4CYP2D6*4 InactiveInactive 1212--2121 11 22 11--44

CYP2D6*5CYP2D6*5 No enzymeNo enzyme 22--77 66 44 11--33

CYP2D6*10CYP2D6*10 UnstableUnstable 11--22 5151 66 33--99

CYP2D6*17CYP2D6*17 ReducedReducedaffinityaffinity 00 NDND 3434 33--99

Ingelman-Sundberg et al., 1999

Struttura degli antimetaboliti usati nellaterapia di alcune forme di leucemia ocome immunosoppressori

TPMT metabolizza tale sostanze: mercaptopurina, azatioprine tioguanidina,ma non si conosce il metabolita fisiologico. Sono antimetaboliti, si intercalanonel DNA e inibiscono la sintesi delle purine

Perchè alcuni soggetti sono sensibili aqueste molecole?

In particolare si riporta che trapiantati ebimbi con leucemie sviluppavano infezionie morivano

Esistono numerose varianti alleliche diTPMT

Determinati soggetti presentano ridotto enzima a causadei polimorfismi che modificano la struttura dell’enzimacon conseguente instabilità e/o degradazionedell’enzima stesso.

E sufficiente diminuire la mercaptopurina nei bimbileucemici se si conosce che sono portatori di un allelepolimorfico.

Il soggetto risponde benissimo senza avere leucopenia.

I soggetti polimorfici per TPMT sviluppano tumoriintracranici: è quindi importantissimo prima di dargli ilfarmaco conoscere il loro profilo farmacogenetico.

Treatment - Polymorphism associations 1

TREATMENT POLYMORPHISM

Fluoropyrimidines DPYD IVS14+1G>ATSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C

Methotrexate ABCC2 C24TTSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C

Irinotecan UGT1A1*28CYP3A4*1BCYP3A5*3ABCB1 C3435T

5-FU: fluoropyrimidine

5-fluorouracil (5-FU) and its derivatives remain some ofthe most commonly prescribed chemotherapy agents.

Approximately 5% of administered 5-FU undergoesanabolism into cytotoxic nucleotides responsible for itsantitumor activity, whereas the other 80%–95% undergoescatabolism into biologically inactive metabolites that areexcreted in the urine and bile.

Dihydropyrimidine dehydrogenase (DPD) catalyzes therate-limiting step in 5-FU catabolism a 5FDHU (5Fluoro-5,6diidrouracile); therefore, variability in this enzyme activityis one of the major factors that influences systemicexposure to fluoro-deoxyuridine monophosphate (FdUMP)and the incidence of adverse effects to 5-FU.

DPYD – Dihydropyrimidine dehydrogenase

Activity: Initial and rate-limiting enzyme in the

catabolism of 5-fluorouracil.

Polymorfism: IVS14+1G>A

The G to A transition in the splice donor site causes the

skipping of exon 14, leading to a truncated protein with

consequent decreased DPYD activity.

Cancer patients, DPYD mutant or heterozygous, with a

complete or nearly complete deficiency of this enzyme

suffered from severe toxicity, including death, following

the administration of 5FU.

TYMS – Thymidylate synthetase

Activity: Important for DNA replication and repair (and

timidina) and primary target for 5-fluorouracil and

capecitabine.

Polymorphism: variable number of tandem repeats

(VNTR) of 28bp (≥ 3 instead of 2) in the promoter region

(TSER).

Homozygous 3R/3R cells overexpress TYMS mRNA

compared with homozygous 2R/2R cells -> possible

chemoresistance.

Low TYMS mRNA expression levels in normal tissue of

patients with the 2R/2R genotype is associated with a

higher risk of cytotoxic effects of 5-FU.

MTHFR – 5,10-methylenetetrahydrofolate reductase(NADPH)

• Activity: It catalyzes the conversion of 5,10-methyleneTHF

in 5-methylTHF. 5,10-methyleneTHF is necessary for DNA

synthesis and maintaining an equilibrate nucleotidic pool.

5-methylTHF is necessary for maintaining the correct DNA

methylation pattern.

• Polymorphisms: 677C>T and 1298A>C: both mutations in

the heterozygous or homozygous state correlate with

reduced enzyme activity and increased thermolability.

MTHFR – 5,10-methylenetetrahydrofolate reductase

(NADPH)

• MTHFR facilitates the formation of the ternary complex 5FU-

TYMS-5,10-methyleneTHF, through which fluoropyrimidines

exert their antineoplastic activity.

• Patients treated with 5-FU, whose MTHFR was mutated, were

significantly at higher risk of toxicity.

Treatment - Polymorphism associations 1

TREATMENT POLYMORPHISM

Fluoropyrimidines DPYD IVS14+1G>ATSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C

Methotrexate ABCC2 C24TTSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C

Irinotecan UGT1A1*28CYP3A4*1BCYP3A5*3ABCB1 C3435T

Irinotecan (Camptosar) is a semisyntheticanalogue of camptothecin and requires metabolicactivation by carboxylesterase to form theactive metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), which in turninhibits topoisomerase-I.

SN-38 is further detoxified via formation of SN-38 glucuronide (SN38G). Irinotecan has potentantitumor activity against a wide range oftumors, and it is one of the most commonlyprescribed chemotherapy agents.Diarrhea and myelosuppression are thedose-limiting toxicities of irinotecan andinterfere with optimal utilization of this importantdrug.

CYP3A4

• CYP3A4 is a monooxygenase that metabolises, throughhydroxylation, tobacco, endogenous steroids and numerousanti-cancer agents.

• The oxidative pathway of irinotecan catalysed by CYP3A4and CYP3A5 result in the formation of inactivemetabolites.

• Polymorphism: -392A>G (allelic variant CYP3A4*1B)• The CYP3A4*1B polymorphism has been associated with

enhanced CYP3A4 expression.• Patients carrying the CYP3A4*1B allele may have

enhanced irinotecan clearance and may beunderexposed.

CYP3A5

Polymorphism: 22893A>G (allelic variant CYP3A5*3)The CYP3A5*3 allele leads to an alternative splicing thatresults in a truncated, inactive protein.Approx. 70% to 90% of Caucasians are homozygousvariant for CYP3A5*3 and thus are deficient in functionallyactive CYP3A5. Patients bearing this mutation have highertoxicity when exposed to the drug.

The wild type allele, CYP3A5*1 is associated totranscript stabilisation and strong increasing of proteinexpression.Patients carrying the CYP3A5*1 allele may have enhancedirinotecan clearance and may be underexposed.

UGT1A1 – UDP glucoronosyltransferase 1A1

• UGT1A1 is involved in glucuronidation of antineoplasticdrugs such as SN38, the active metabolite of irinotecan, aswell as estrogens and their metabolites. UGT1A1 conferspolarity to xenobiotics or endogenous substrates to beeliminated through urine and bile.

• Polymorphism: A(TA)6TAA>A(TA)7TAA (allelic variantUGT1A1*28): the increase in the number of (TA) repeats inthe TATA box region of the UGT1A1 promoter is associatedwith a reduced expression of the gene.

• The reduced glucuronidation rate of SN38, due to thepolymorphism, leads to increase its toxic effect.

(carboxilesterasi)

UGT1A1 TA repeat genotype altersirinotecan neutropenic/activity

35.7

16.3

8.6

0

5

1015

20

25

30

3540

45

50

6/6 6/7 7/7

P=0.007

UGT1A1 genotype

% g

rad

e 4

/5

neu

tro

pen

ia

N=524McLeod H. et al, 2003.

The UGT1A1*28 polymorphism, veryfrequent among Caucasians, has been

reported to be associated with an increasedhematological toxicity (severe neutropenia)in colorectal patients following irinotecan

chemotherapy.

The US FDA has issued recommendations toThe US FDA has issued recommendations toconsider the UGT1A1*28 polymorphismconsider the UGT1A1*28 polymorphism

before startingbefore starting irinotecanirinotecan chemotherapy.chemotherapy.

ABCB1 – ATP-binding cassette, sub-family B(MDR/TAP), member 1 o MDR1 (Multi-DrugResistance) P-glycoprotein

P-glycoprotein is expressed in cells lining the intestine,the biliary tract and the blood-brain barrier and has animportant role in the prevention of absorption and theexcretion of potentially toxic metabolites andxenobiotics.ABCB1 is thought to be one of the most importantproteins involved in irinotecan elimination.

Polymorphism: 1236C>T: the SNP may have anindirect effect such as altering RNA stability.The homozygous T allele of the ABCB1 polymorphismwas associated with significantly increased exposureto irinotecan and its active metabolite SN-38.

Polimorfismi geneticiin bersagli primari di farmaci

ed effetti sulla rispostafarmacologica

Polimorfismi geneticiin bersagli primari di farmaci

ed effetti sulla rispostafarmacologica

Receptor/targetReceptor/target

b2-Adrenergic receptorb2-Adrenergic receptor

MedicationMedication

AlbuterolAlbuterol

5-Lipoxygenase promoter5-Lipoxygenase promoter ABT-761(zileuton)ABT-761(zileuton)

Angiotensin-converting enzyme(ACE)Angiotensin-converting enzyme(ACE)

Enalapril,lisinopril,captopril

Enalapril,lisinopril,captopril

Cholesteryl ester transferproteinCholesteryl ester transferprotein

PravastatinPravastatin

StromelysinStromelysin PravastatinPravastatin

Angiotensin-II T receptorAngiotensin-II T receptor PerindoprilnitrendipinePerindoprilnitrendipine

Receptor/targetReceptor/target

Sulfonylurea receptorSulfonylurea receptor

MedicationMedication

TolbutamideTolbutamide

5-Hydroxytryptamine 2C receptor5-Hydroxytryptamine 2C receptor ClozapineClozapine

Serotonin transporter promoterSerotonin transporter promoter FluvoxamineFluvoxamine

Vitamin D receptorVitamin D receptor 1,25-Dihydroxyvitamin D31,25-Dihydroxyvitamin D3

5-Hydroxytryptamine 2A receptor5-Hydroxytryptamine 2A receptor Clozapineand otherneuroleptics

Clozapineand otherneuroleptics

Dopamine D2 and D3 receptorsDopamine D2 and D3 receptors AntipsychoticsAntipsychotics

Glucocorticoid receptorGlucocorticoid receptor DexamethasoneDexamethasone

Receptor/targetReceptor/target

Nicotinic receptorNicotinic receptor

MedicationMedication

Acetylcholine(-) nicotineAcetylcholine(-) nicotine

Delta opioid receptorDelta opioid receptor HeroinHeroin

Potassium channelsPotassium channels

HERGHERG QuinidineQuinidine

CisaprideCisapride

KvLQT1KvLQT1 Terfenadine,disopyramidemeflaquine

Terfenadine,disopyramidemeflaquine

hHCNE2hHCNE2 ClarithromycinClarithromycin

Receptor/targetReceptor/target

Sodium channelsSodium channels

MedicationMedication

SCN5ASCN5A MexiletineMexiletine

LithiumLithium

Cyclosporin ACyclosporin A

TacrineTacrine

Inositol-p1pInositol-p1p

HLA-DRB1HLA-DRB1

Apolipoprotein E4Apolipoprotein E4

Ryanodine receptorRyanodine receptor Halothane orsuccinylcholineHalothane orsuccinylcholine

ProthrombinProthrombin OralcontraceptivesOralcontraceptives

Peroxisome proliferator-activatedreceptorPeroxisome proliferator-activatedreceptor

InsulinInsulin

1 ARSer or Gly1 AR

Ser or Gly

2 ARArg or Gly2 AR

Arg or Gly

2 ARGlnor Glu

2 ARGlnor Glu

2 ARMet or Val2 AR

Met or Val 2 ARThr or Ile2 AR

Thr or Ile

1 ARGly

or Arg

1 ARGly

or Arg

16164949

2727

3434

164164

389389

Effetti farmacologici delpolimorfismo in posizione 389

del recettore Beta-1

Effetti farmacologici delpolimorfismo in posizione 389

del recettore Beta-1

Effetti farmacologici delpolimorfismi nelle posizioni164, 16 e 27 del recettore

Beta-2

Effetti farmacologici delpolimorfismi nelle posizioni164, 16 e 27 del recettore

Beta-2

La cascata dell’acidoarachidonico

La cascata dell’acidoarachidonico

Associazione farmacogeneticatra il genotipo del promotore

di Alox5 e la rispostaal trattamento anti-asma

Associazione farmacogeneticatra il genotipo del promotore

di Alox5 e la rispostaal trattamento anti-asma

Sp1

Sp1

Sp1

Sp1

Sp1

Sp1

Sp1

Sp1

Sp1

IL PROMOTORE DEL GENE ALOX5

Allele frequenciesAllele frequencies

Allele typeaAllele typea

FrequencyFrequency33

44

55

66

0.0380.038

0.1720.172

0.7720.772

0.0180.018

Gli studi farmacogeneticipossono essere

di tipo

diretto o indiretto

Gli studi farmacogeneticipossono essere

di tipo

diretto o indiretto

Gli studi direttiGli studi diretti

Sono finalizzati all’identificazionedi varianti alleliche nelle regionicodificanti (cSNP) o, regolatorie

(pSNP), di geni prescelti “a priori”sulla base delle conoscenze

a disposizione

Sono finalizzati all’identificazionedi varianti alleliche nelle regionicodificanti (cSNP) o, regolatorie

(pSNP), di geni prescelti “a priori”sulla base delle conoscenze

a disposizione

I polimorfismio

gli aplotipi(combinazione di

polimorfismi)identificati vengono utilizzati

in studi diassociazione allelica

per verificarese essi correlino con un determinato

profilo farmacogenetico

Crossing-over tra cromosomiomologhi durante la meiosi

Crossing-over tra cromosomiomologhi durante la meiosi

Meccanismo di insorgenza di“Linkage disequilibrium”

Meccanismo di insorgenza di“Linkage disequilibrium”

Gli studi indirettiGli studi indiretti

Si avvalgono di SNPs anonimi localizzatisu tutto il genoma, particolarmente nelDNA intergenico, sfruttando la loroassociazione in “Linkage disequilibrium”con i geni responsabili dello specificoprofilo farmacogenetico

Si avvalgono di SNPs anonimi localizzatisu tutto il genoma, particolarmente nelDNA intergenico, sfruttando la loroassociazione in “Linkage disequilibrium”con i geni responsabili dello specificoprofilo farmacogenetico

La Farmacogenetica è un processoche si sviluppa in 3 fasi distinteLa Farmacogenetica è un processoche si sviluppa in 3 fasi distinte

La fase della scoperta ecatalogazione degli SNPs

La fase della scoperta ecatalogazione degli SNPs

La fase della ricerca di correlazionitra la presenza di definiti SNPS(Aplotipi) e determinati profilifarmacogenetici

La fase della ricerca di correlazionitra la presenza di definiti SNPS(Aplotipi) e determinati profilifarmacogenetici

La fase diagnostica La fase diagnostica

Current Methods for genetictesting

• By phenotype: metabolic probe drug or Western blot• By PCR with mutation-specific endonuclease• By PCR and allele-specific hybrization• By oligonucleotide chip hybridization• By laser lithography - guided oligonucleotide chip

hybridization.• By rapid throughput pyrosequencing• Taqman probe screening

Estimated cost to the patient ofGenetic Tests in Clinical Practice

• By simple PCR for one mutation: ~$10• For 50 mutations: ~$150• By Chip for ~ 20 mutations: ~ $70• By Chip for 100 mutations: ~ $250

Clinical PharmacogeneticsSummary

• A good phenotyping probe is critical• Genetic tests need validation just as any other tests• A potent inhibitor can mimic a genetic polymorphism• Not all genetic polymorphisms have a phenotypic

correlate, or clinical effect• The clinical relevance of genetic polymorphisms is

greatest with drugs of narrow therapeutic range, butnot confined to them

• The cost of genetic testing is not likely to be limiting

Pharmacogenetics Websites

• www.pharmgkb.org• The SNP consortium: http://brie2.cshl.org• The Human Genome:

www.ncbi.nlm.nih.gov/genome/guide/H_sapiens.html• CYP alleles: www.imm.ki.se/CYPalleles/• Drug Interactions: www.drug-interactions.com

PHARMACOGENOMICS

• PHARMACOGENOMICS is defined as the study of the interaction of anindividual's genetic makeup and response to a drug.

• The key distinction between pharmacogenetics and pharmacogenomics is that theformer describes the study of variability in drug responses attributed to individualgenes and the latter describes as a study of the entire genome related to drugresponse.

• The expectation is that inherited variation at the DNA level results in functionalvariation in the gene products which will play an essential role in determining thevariability in responses, both therapeutic and adverse, to a drug.

• Automated analysis of genome-wide SNPs allows the possibility of identifyinggenes involved in drug metabolism, transport and receptors, which are likely toplay a role in determining the variability in efficacy, side-effects and toxicity of adrug.

ECOGENETICS

• An extension of pharmacogenetics is the study of genetically determineddifferences in susceptibility to the action of physical, chemicaland infectious agents in the environment.

• This has been referred to as ecogenetics.• Such differences in susceptibility can be either unifactorial or

multifactorial in causation.

Finalità

• Incentivare la ricerca farmacologica sulle basi genetiche dellarisposta individuale ai farmaci

• Farsi promotore di linee guida per un uso etico dellafarmacogenetica

• Promuovere presso gli operatori sanitari la Farmacogeneticaquale strumento per l’ottimizzazione dell’intervento terapeutico

• Stimolare e cooperare con le autorità sanitarie per un uso dellaFarmacogenetica in prospettiva farmacoeconomica

• Integrare le esigenze della Farmacogenetica di base e clinicacon le prospettive ed aspettative dell’industria farmaceutica

• Contribuire alla formazione di esperti nel settore

• Sensibilizzare l’opinione pubblica circa l’uso dellaFarmacogenetica per una medicina personalizzata.

società italiana di farmacologia (SIF)Gruppo di lavoro sulla Farmacogenetica