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

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HETEROGENEIDADE DA POPULAÇÃO BRASILEIRA: Implicações farmacogenéticas HETEROGENEIDADE DA POPULA HETEROGENEIDADE DA POPULA Ç Ç ÃO BRASILEIRA: ÃO BRASILEIRA: Implica Implica ç ç ões ões farmacogen farmacogen é é ticas ticas Guilherme Suarez-Kurtz Instituto Nacional de Câncer Rio de Janeiro - Brasil Guilherme Suarez-Kurtz Instituto Nacional de Câncer Rio de Janeiro - Brasil SBMF-DIA, São Paulo 2010
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Transcript of HETEROGENEIDADE DA POPULAÇÃO BRASILEIRA: Implicações ... · PDF...

  • HETEROGENEIDADE DA POPULAO BRASILEIRA:

    Implicaes farmacogenticas

    HETEROGENEIDADE DA POPULAHETEROGENEIDADE DA POPULAO BRASILEIRA: O BRASILEIRA:

    ImplicaImplicaes es farmacogenfarmacogenticasticas

    Guilherme Suarez-KurtzInstituto Nacional de Cncer

    Rio de Janeiro - Brasil

    Guilherme Suarez-KurtzInstituto Nacional de Cncer

    Rio de Janeiro - Brasil

    SBMF-DIA, So Paulo 2010

  • A farmacogentica estuda a variabilidade inter-individual

    na resposta aos medicamentos, devida a fatores genticos.

    Kalow, 1962

    Farmacogentica ~ farmacogenmica = PGx

  • A PGx estuda a variabilidade inter-individual

    na resposta aos medicamentos, devida a fatores genticos.

  • Variabilidade inter-individual na concentrao 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%

    Farmacogentica

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

    4.17%4.17%

    4.17%

    37.5%

    Farmacogentica

    GENTICA

    Disfuno de rgoPatologiasGravidez/lactaoSexoEtnia/raa

    InteraesTabagismoUso de lcoolDietaAdernciaRegulatriosOutros

    Prtica mdica

    Fatores genticos e no-genticos

  • 4.17%4.17%4.17%4.17%4.17%4.17%

    4.17%4.17%.17%

    37.5%

    Monognico

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

    37.5%

    Oligognico

    VKORC1CYP2C9

    Varfarina

    succinilcolina apnia 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%

    Polignico

    Neurolpticos

  • Cooper et al., Blood 2008

    Genome-Wide Association Studies (GWAS) Associao com a ao 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, BSArace/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

    Ilhus

    Fortaleza

    Belm

    Refargen study of PGx polymorphisms in Brazilians

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

    Amarela 1.101 0,58Indgena 536 0,28

    Sem declarao 130 0,07

    Cor ou raa populao

  • 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 AmerindianAfrican

    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