PHARMACOGENETICS, POPULATION STRUCTURE AND ADMIXTURE Guilherme Suarez-Kurtz Rio de Janeiro - Brazil Guilherme Suarez-Kurtz Rio de Janeiro - Brazil RS-ICSU-IAP.

PHARMACOGENETICS, PHARMACOGENETICS,

POPULATION STRUCTURE AND POPULATION STRUCTURE AND

ADMIXTUREADMIXTURE

PHARMACOGENETICS, PHARMACOGENETICS,

POPULATION STRUCTURE AND POPULATION STRUCTURE AND

ADMIXTUREADMIXTURE

Guilherme Suarez-KurtzRio de Janeiro - Brazil

Guilherme Suarez-KurtzRio de Janeiro - Brazil

RS-ICSU-IAP 2006

Pharmacogenetics

deals with drug

responses

(therapeutic or

adverse) and their

modification by

hereditary factors.

P H A R M A C O G E N E T I C S

P H A R M A C O G E N I C S

Pharmacogenomics is pharmacogenetics with two SNPs

O MO M

one drug/one dose fits all

THE CURRENT PARADIGM

THE PHARMACOGENETICS PROMISE

personalised therapy ”paradigm-disrupting”

PHARMACOGENETIC DATABASES

• Population frequencies of many polymorphic genes of

pharmacogenetic interest depend on race or ethnic

specificity.

• Information about ethnic specificity has become an

integral part of pharmacogenetic research.

DRUG

ACTIVE/inactive metabolite

Phase I Cytochrome P450 (CYP)

DRUG and XENOBIOTIC METABOLISM

Phase II Glutathione-S-transferases (GST)

INACTIVEmetabolite

0

5

1 0

1 5

2 0

2 5

3 0

C Y P 2 D 6 * 1 7 C Y P 2 C 9 * 3

Alle

le f

req

ue

ncy

(%

)

E u r o p e a n

C Y P 2 A 6 * 4 A

S u b - S a h a r a n A f r i c a n

E a s t A s i a n

Continental populations

Population stratification in Singapore

Chowbay et al., 2005

0

10

20

30

40

50

60

70

GSTM1-null

F

req

uen

cy (

%)

Indian Chinese Malay

CYP3A5*1

Stratification: subpopulations

Data from Park et al., 2000; Tetlow et al., 2004

0

20

40

60

Gen

otyp

e fr

eque

ncy

(%)

*A/*A *A/*B *B/*B

GSTM3 (6bp deletion)

African Bantu White AmericanAfrican-American

Data from Park et al., 2000; Medeiros et al., 2004; Suarez-Kurtz et al., 2006

0

20

40

60

Gen

otyp

e fr

eque

ncy

(%)

*A/*A *A/*B *B/*B

GSTM3 (6bp deletion)

African Bantu PortugueseBlack Brazilians

Stratification: admixture

GENETIC ADMIXTURE: the mixing of two

or more genetically differentiated

populations.

“Because of considerable genetic

admixture in most human

populations...”

Nebert and Menon, Pharmacogenomics

2001

1500 ~ 2.5 M Amerindians

1500 - 1808 ~ 0.5 M Portuguese

1851 - 1960 ~ 4.5 M immigrants Portugal 1.7 M

Italy 1.6 M Spain 0.7 M Germany 0.25 M

1551 - 1880 ~ 3.6 M Enslaved Africans

Sources of the tri-hybrid Brazilian population

Suarez-Kurtz <

-20

-15

-10

-5

0

5

10

15

20

-20

-15

-10

-5

0

5

10

15

20

S. Tomé Black Interm. White Portugal

-20

-15

-10

-5

0

5

10

15

20

-20

-15

-10

-5

0

5

10

15

20

S. Tomé Black Interm. White Portugal

Afr

ica

n a

nce

str

y in

dex

Brazilians in southeast rural area

Parra et al., 2003

6% 38% 53%

-20

-15

-10

-5

0

5

10

15

20

-20

-15

-10

-5

0

5

10

15

20

S. Tomé Black Interm. White Portugal

-20

-15

-10

-5

0

5

10

15

20

-20

-15

-10

-5

0

5

10

15

20

S. Tomé Black Interm. White Portugal

Afr

ica

n a

nce

str

y in

dex

Brazilians in southeast rural area

Parra et al., 2003

-20

-15

-10

-5

0

5

10

15

20

-20

-15

-10

-5

0

5

10

15

20

S. Tomé Black Interm. White Portugal

-20

-15

-10

-5

0

5

10

15

20

-20

-15

-10

-5

0

5

10

15

20

S. Tomé Black Interm. White Portugal

Afr

ica

n a

nce

str

y in

dex

Brazilians in southeast rural area

Parra et al., 2003

6% 38% 53%

0 . 0

0 . 5

1 . 0

0 . 0

0 . 5

1 . 0

0 . 0

0 . 5

1 . 0

B l a c k

A m e r i n d i a n A f r i c a n E u r o p e a n

W h i t e

I n t e r m e d i a t e

ADMIXTURE IN BRAZILIANS

Suarez-Kurtz et al., Clin Pharm Ther, 2005 based on 40 indel AIM set developed by Sergio D. J. Pena

European

African Amerindian

Self-declared WHITE Brazilians

European

African Amerindian

Self-declared BLACK Brazilians

Pena et al. 2006

0.0

0.1

0.2

0.3

0.4G

enot

ype

fre

quen

cy

GSTM3*B/*B

White Black

African ancestry (%)

< 25 25 - 50 50 -75 >75

E. Parra et al., Nat Genet 2004African-CaribbeansAfrican-AmericansPuerto RicansHispanicsMexicans

*

a

Jorde & Wooding, Nat Genet 2004, adapted from Bamshad et al., Am J Hum Genet 2003

Jorde & Wooding, Nat Genet 2004, adapted from Bamshad et al., Am J Hum Genet 2003

Serre & Pääbo, 2004

African

European

Asian

OceanianNative American

Serre & Pääbo, Genome Res 2004

Lamba et al. Clin Pharm Ther 2000

CYP2C19*2CYP2C19*3

Worldwide gradients in CYP2C19 variant allele frequency

Sub-S

ahar

an A

frica

n

Africa

n-Am

erica

n

Black B

razil

ian

Europ

ean

Whit

e Am

erica

n

Whit

e Bra

zilian

Chines

e

Japa

nese

Mala

ysian

Siberia

n

Map

uche

(Chil

e)

Six gr

oups

(Bra

zil)

0

10

20

30

40

50

60

70

80

90

100

Fre

qu

en

cy C

YP

1A

1*2

C (

%)

X Axis Title

Surui

FREQUENCY DISTRIBUTION OF CYP2C9*5

Data from Dickman et al. (2001), Xie et al. (2003, and references therein), Llerena et al. (2004).

Population CYP2C9*5

North-American

African-American 1.7

European-American 0

Mexican-American 0

African

Beninese, Tanzanian 0.8-1.8

Ethiopian 0

European 0

Asian 0

> G

> Glu

G/C

Suarez-Kurtz et al. Clin Pharm Ther, 2005

92% European 7.5% African 0.5% Amerindian

mtDNA L3d

Father

Mother

*5*1

CYP2C9 alleles

I WW

I W

“Race/ethnic” categorization/discrimination: appearance vs. descent