HETEROGENEIDADE DA POPULAÇÃO BRASILEIRA: Implicações ... · PDF...

HETEROGENEIDADE DA POPULAÇÃO BRASILEIRA:

Implicações farmacogenéticas

HETEROGENEIDADE DA POPULAHETEROGENEIDADE DA POPULAÇÇÃO BRASILEIRA: ÃO BRASILEIRA:

ImplicaImplicaçções ões farmacogenfarmacogenééticasticas

Guilherme Suarez-KurtzInstituto Nacional de Câncer

Rio de Janeiro - Brasil

Guilherme Suarez-KurtzInstituto Nacional de Câncer

Rio de Janeiro - Brasil

SBMF-DIA, São Paulo 2010

A farmacogenética estuda a variabilidade inter-individual

na resposta aos medicamentos, devida a fatores genéticos.

Kalow, 1962

Farmacogenética ~ farmacogenômica = PGx

A PGx estuda a variabilidade inter-individual

na resposta aos medicamentos, devida a fatores genéticos.

Variabilidade inter-individual na concentração de lopinavir no plasma

Estrela et al.,

Pharmacogenomics, 2009

26 X

0

4000

8000

12000

16000

Con

cent

ratio

nof

lopi

navi

rin

plas

ma

(ng/

ml)

Individuals

110 HIV+ adult males

LPV/RTV 400/100 mg/daily

Fatores que modulam a resposta aos medicamentos

Huang et al, CPT 2008

Idade

6.25%6.25%6.25%6.25%

6.25%

6.25%6.25% 6.25% 6.25%

6.25%

Farmacogenética

4.17%4.17%4.17%4.17%4.17%4.17%4.17%

4.17%4.17%

37.5%

Farmacogenética

GENÉTICA

Disfunção de órgãoPatologiasGravidez/lactaçãoSexoEtnia/raça

InteraçõesTabagismoUso de álcoolDietaAderênciaRegulatóriosOutros

Prática médica

Fatores genéticos e não-genéticos

4.17%4.17%4.17%4.17%4.17%4.17%4.17%

4.17%.17%

37.5%

Monogênico

4.17%4.17%4.17%4.17%4.17%4.17%

37.5%

Oligogênico

VKORC1CYP2C9

Varfarina

succinilcolina apnéia prolongada BuCHestatinas miotoxicidade SCLO1B1carbamazepina Stevens-Johnson HLA-B*1502abacavir hiperssensibilidade HLA-B*5701

4.17%4.17%4.17%4.17%4.17%4.17%

37.5%

Poligênico

Neurolépticos

Cooper et al., Blood 2008

Genome-Wide Association Studies (GWAS) Associação com a ação anticoagulante da varfarina

Jones & McLeod, 2009

Role of CYP2C9 and VKORC1 enzymes in warfarin pharmacology

CYP2C9

VKORC1

S-warfarin

Widely used anticoagulant

Large inter-individual dose range

Warfarin: a “model” PGx target

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 00

1 0

2 0

3 0

4 0

5 0

6 0

Num

ber o

f pat

ient

s

W a r fa r in w e e k ly d o s e ( m g )

FDA approved doses

Widely used anticoagulant

Large inter-individual dose range

Narrow therapeutic index

insufficient dose: thrombosisexcessive dose: haemorrhage/bleeding

Warfarin: a “model” PGx target

Widely used anticoagulant

Large inter-individual dose range

Narrow therapeutic index

insufficient dose: thrombosisexcessive dose: haemorrhage/bleeding

INR = biomarker of anticoagulant effect

Oligogenic modulation of clinical response

Warfarin: a “model” PGx target

Warfarin PGx in Brazilian patients

Study cohort

• 390 unrelated, adult outpatients of Anticoagulation Unit, National Cardiology Institute, Rio de Janeiro

• Stable warfarin dose (3 INRs in the range 2 - 3/3.5)

• Self-identified as White (196), Brown (118) or Black (176)

• Indication: Valve prosthesis (40%), AF (35%), prosthesisplus AF (18%), thromboembolism (18%)

, 2009

N =390 cardiovascular patients

Stable therapy w/ warfarin

26 X

0

20

40

60

80

War

farin

dose

(m

g/w

eek)

Patients

Warfarin PGx: inter-individual variability in dose

CYP2C9 polymorphisms modulate warfarin stable dose

0 1 20

10

20

30

40

50W

arfa

rin w

eekl

y do

se (m

g)

Number of CYP2C9 variant alleles

N = 390P = .004

(*2, *3, *5)

Perini et al., 2008

VKORC1 3673G>A modulates warfarin stable dose

AA GA GG0

10

20

30

40

50

War

farin

wee

kly

dose

(mg)

VKORC1 3673G>A genotype

N = 390P < .0001

Perini et al., 2008

Combined modulation of warfarin dose byCYP2C9 and VKORC1 polymorphisms

0

10

20

30

40

50

60

GG GA AA GG GA AA GG GA AA

War

farin

dose

(mg/

wee

k)

CYP2C9 *1/*1 *1/*3 *1/*2 VKORC1 3673

Perini et al., 2008

N = 390

P < .0001

Combined modulation of warfarin dose byCYP2C9 and VKORC1 polymorphisms

Development of warfarin PGx dosing algorithms

Variables

PharmacogeneticVKORC1CYP2C9

Demographicage, sexweight, height, BSA“race/color”

Clinicalindicationconcomitant drugs

Univariateanalysis

Multivariateanalysis

Dosingalgorithm

Two-step procedure

VKORC1 3673G>A

CYP2C9*2, *3, *5

amiodarone

weight

treatment indication

age

simvastatin

Covariates

Partial r2

Covariates associated with warfarin dose in Brazilian patients

A PGx warfarin dosing algorithm for Brazilians

=

Warfarin weekly dose (mg)

Perini et al., 2008

r = 0.72N = 390

0 20 40 60 800

20

40

60

80

0 20 40 60 800

20

40

60

80

0 20 40 60 800

20

40

60

80

Obs

erve

d do

se (m

g/w

eek)

Predicted dose (mg/week)

r = 0.51bias = 5.9%

2

A PGx warfarin dosing algorithm for Brazilians

Perini et al., 2008

0 20 40 60 800

20

40

60

80

0 20 40 60 800

20

40

60

80

0 20 40 60 800

20

40

60

80

Algorithm-predicted warfarin dose (mg/week)

Obs

erve

d w

arfa

rindo

se (m

g/w

eek)

r = 0.61bias = 5.2%

2

N =390

Suarez-Kurtz et al., Blood 2009

A PGx algorithm including INR as a covariate

2

A “global” warfarin PGx algorithm

IWPC, 2009

ageheight

weight

VKORC1

CYP2C9

Drug interaction

Race

A “global” warfarin PGx algorithm

IWPC, 2009

Comparison of PGx warfarin algorithms

0

0.1

0.2

0.3

0.4

0.5

Alle

lefre

quen

cy

Portuguese (European)Mozambican/Angolan (African)

3673A *2, *3VKORC1 CYP2C9

Why warfarin PGx algorithms perform poorlyin Africans and African-Americans ?

0

0.1

0.2

0.3

0.4

0.5

Alle

lefre

quen

cy

PortugueseWhite BrazilianBlack BrazilianMozambican/Angolan

3673A *2, *3VKORC1 CYP2C9

Why warfarin PGx algorithms perform poorlyin Africans and African-Americans,

but perform equally well in white and black Brazilians ?

www.refargen.org.br

North14.6

Northeast51.5

Southeast77.9

South26.7

Center-West13.2

Porto Alegre

Joinville

Rio de Janeiro

Ilhéus

Fortaleza

Belém

Refargen study of PGx polymorphisms in Brazilians

N %Branca 92.003 48,43Parda 83.196 43,80Preta 12.987 6,84

Amarela 1.101 0,58Indígena 536 0,28

Sem declaração 130 0,07

Cor ou raça população

Refargen study of PGx polymorphisms in BraziliansVKORC1

SNP Genebank coordinate rs code

3673G>A -1639G>A rs99232315808T>G 497T>G rs28847376853G>C 1542G>C rs80508949041G>A 3730G>A rs7294

Study cohorts: 1037 Brazilians90 Portuguese

150 Mozambicans80 Angolans

3673A 5808G 6853C 9041A0,0

0,1

0,2

0,3

0,4

0,5

Alle

le f

requ

ency

VKORC1 polymorphism

P = 0.76P = 0.02 P = 0.61 White (342) Brown (350) Black (345)

P = 0.001

Allele distribution in the overall Brazilian cohort

Allele distribution according to Color and geographical region

0.5

0.4

0.3

0.2

0.1

0

Alle

le f

requ

ency

Alle

le f

requ

ency

0.4

0.3

0.2

0.1

0

This represents a caveat against ascribing PGx polymorphisms´ frequencies

for “Brazilians” based on data from one or more Color strata

recruited at a given region.

PGx implications

The distribution of VKORC1 polymorphisms among Brazilians varies

across geographical regions and within self-reported Color categories.

Biogeographical ancestry of BLACK Brazilians

1.0

Indi

vidu

al p

ropo

rtion

of g

enet

ican

cest

ry

0.8

0.6

0.4

0.2

0

50 100 150 200 250 300

Individuals

Black Brazilians Amerindian

African

European

20 40 60 80 1000,0

0,2

0,4

0,6

0,8

1,0

Pro

porti

on o

f gen

etic

anc

estry

E F G

120 140 160 180 200

Individuals220 240 260 280 300 320

I I I I I I50 100 150 200 250 300

Individuals

1.0

Indi

vidu

al p

ropo

rtion

of g

enet

ican

cest

ry

0.8

0.6

0.4

0.2

0

White Brazilians Amerindian

African

European

Biogeographical ancestry of WHITE Brazilians

Brown Brazilians Amerindian

African

European

1.0

Indi

vidu

al p

ropo

rtion

of g

enet

ican

cest

ry

0.8

0.6

0.4

0.2

0

50 100 150 200 250 300

Individuals

Biogeographical ancestry of BROWN Brazilians

Brazilians vs. Portuguese and Africans

* P < .02** P < .0001

PortugueseBraz. >0.9 EuropeanBraz >0.8 AfricanAngolan/Mozambican

0

10

20

30

40

50

VKORC1 polymorphisms

Min

or a

llele

freq

uenc

y (%

)

3673G>A 5808T>G 6853G>C

**

**

*

The frequency of VKORC1 3673G>Avaries continuously with European ancestry

VKO

RC1

3673

A pr

obab

ility

0.4

0.3

0.35

0.25

0.15

0.2

Proportion of European ancestry0 0.2 0.4 0.6 0.8 1.0

The distribution of VKORC1 polymorphisms among Brazilians varies

across geographical regions, within self-reported Color categories and

according to individual proportions of European/African ancestry.

PGx implications

The heterogeneity of the Brazilian population must be taken into account

in the design and interpretation of PGx clinical trials

and dealt with as a continuous variable.

This is likely to apply to other admixed populations of the Americas.

Pelé e Bobby Moore

Copa do Mundo de 1970,

Brasil 1 x 0 Inglaterra

Barreira brasileira...

... and preserving continuation of the species

Barreira brasileira... protegendo a miscigenação/heterogenidade dos brasileiros