pharmacogenetics, population structure and admixture guilherme suarez-kurtz rio de janeiro - brazil...
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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
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
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
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
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