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