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“Genomics in Patients with Hispanic ancestry” - Pharmacogenetics in Hispanics and Its clinical implications -
Adrián LLerena MD PhD
Clinical Research Centre University Hospital. Faculty of Medicine. University of Extremadura, Badajoz, Spain
08.10.2012
EMA Workshop on Pharmacogenomics: from science to clinical care
October 8-9, 2012
Ibero-America is a term used since the second half of the 19th century to refer collectively to the
countries in the Americas which were formerly colonies of Spain or Portugal.!
600 000 0000 people
Interindividual Variability on Drug Response
Age elderly
children neonates
Weight
Sex
Height
Genotype
Ethnicity
Environmental Factors
diet / smoking / comedications
Pregnancy
Concomitant Disease
Disease Process
CYP2D6
Debrisoquine hydroxylation phenotype (CYP2D6) in the Spanish Population (n=923) (LLerena et al 1993)
CYP2D6 polymorphism in Spaniards (LLerena et al 1993)
Adrián LLerena 2012 [email protected]
CYP2D6
CYP2D6*2xN
CYP2D6*5
Gen multiplication
Incremento actividad
No enzyme Delection
CYP2D6*4
CYP2D6*10
Defect splicing Enzima inactiva
Enzima inestable Pro34Ser
Ser486Thr
CYP2D6*17 Afinidad por el sustrato reducida
Thr107Ile Arg296Cys Ser486Thr
Caucasians Asians Black African Ethiopians and Arabs
CYP2D6*2xN 1 - 5 0 - 2 2 10 - 16 CYP2D6*4 12 - 21 1 2 1 - 4 CYP2D6*5 2 - 7 6 4 1 - 3 CYP2D6*10 1 - 2 51 6 3 - 9 CYP2D6*17 0 ND 34 3 - 9
PMs
RIBEF - Adrián Llerena, Pedro Dorado 2004
Interethnical variability: CYP2D6 gene multiplication (Ultrarapids?)
Interethnic distribution of individuals with CYP2D6 gene duplicated
Magnus Ingelman-Sundberg
4.9%
Ibero American Network of Pharmacogenetics
RIBEF - SIFF
CEIBA Consorcio Europeo Ibero Americano Farmacogenética
Population Pharmacogenetics among LA populations
N= 6479
Achivements:
6 479 healthy volunteers studied
Pheno and Genotype
-2 -1 0 1 20
2
4
6
8
10
12
14
16
18
Cuban-Caucasians
5.3%
0
20
40
60
80
100PMsUMs
5.3%
debrisoquine/4-OH debrisoquine (log 10)
Num
ber
of s
ubje
t cs
Prob
i t (p
erce
n tag
e %
)
-2 -1 0 1 20
2
4
6
8
10
12
14
16
18
Cuban-Mestizos
3.9%
PMs
0
20
40
60
80
100UMs
2.3%
debrisoquine/4-OH debrisoquine (log 10)
Num
ber
of s
ubje
tcs
Prob
it ( p
e rce
nta g
e %
)
-2 -1 0 1 20
2
4
6
8
10
12
14
16
18
Nicaraguan-Amerindians
6.0%
0
20
40
60
80
100PMsUMs
0.0%
debrisoquine/4-OH debrisoquine (log 10)
Num
ber
of s
ubje
tcs
P rob
i t (p
erc e
n tag
e %
)
-2 -1 0 1 20
10
20
30
40
50
60
70
80
90
100
4.9%
0
20
40
60
80
100
PMsSpaniardsUMs
5.2%
debrisoquine/4-OH debrisoquine (log 10)
Num
ber
of s
ubje
t cs
P rob
it (p
erce
n tag
e %
)
LLerena et al; Pharmacogenomics 2011 Adrián LLerena 2012 [email protected]
0%
2.3%
RIFF - Adrián LLerena
Cuban -Caucasians Cuban -Mestizos Nicaraguan -Amerindian CYP2D6 alleles (n=260) (n=252 ) (n=196) wt ( *1 or *2) 0.754 0.663 0.761 *3 0 0 0 *4 0.146 0.143 0.142 *5 0.019 0.016 0.046 *6 0.008 0.012 0 *10 0.004 0.008 0.031 *17 0.027 0.102 0. Duplications wt (*1 or *2) xN 0.038 0.047 0.020 *4xN 0.004 0 0
Frequencies of CYP2D6 variant alleles among Cuban-Caucasian, Cuban-Mestizo, and Nicaraguan-Amerindian populations (n= number of alleles.) Unpublished data from (LLerena, P. Dorado, B. Pérez, I. González, La Habana, R. Ramírez, León, Nicaragua).
Voluntarios sanos
-1.3 -1.0 -0.5 0.0 0.5 1.1 1.5 2.00
5
10
Indice metabólico de debrisoquina (log)
Frecuencia %
CYP2D6 among Hispanics: Spaniards, Cubans, Nicaraguans
RED IBEROAMERICANA DE FARMACOGENETICA
www.ribef.com CEIBA Consortium [email protected]
-1. 2 -1. 1 -1. 0 -0. 9 -0. 8 -0. 7 -0. 6 -0. 5 -0. 4 -0. 3 -0. 2 -0. 1 0. 0 0. 1 0. 2 0. 3 0. 4 0. 5 0. 6 0. 7 0. 8 0. 9 1. 0 1. 1 1. 2 1. 3 1. 40
5
10
15
20
25
30
35
0
20
40
60
80
100
EMs PMs
dextromet horphan/dex trorphan ( log10)
Nu
mbe
r of
su
bjet
c s
Pro
bit (
perc
enta
ge %
)
!
ECUADORIANS
+Eur J Clin Pharmacol 2012)
RED IBEROAMERICANA DE FARMACOGENETICA
www.ribef.com CEIBA Consortium [email protected]
INTERETHNIC DIFFERENCES ON DEBRISOQUINE HYDROXYLAXE POLYMORPHISMS
Japo
nese
s
Kor
eano
sC
hino
s W
ei
Chi
nos
Japo
nese
s
Taila
ndes
esC
hino
s
Chi
nos
Zang
Chi
nos
Finl
ande
ses
Hun
garo
s Finl
ande
ses
Cub
anos
-Bla
ncos
Suec
os
Finl
ande
ses
Finl
ande
ses
Pola
cos
Aust
ralia
nos
Eslo
veno
s
Nor
team
eric
anos
Belg
as Rus
os
Aust
ralia
nos
Nor
team
eric
anos
Suec
osBr
itani
cos Es
toni
os
Suiz
os Suiz
os
Alem
anes
Turc
os Turc
osEs
paño
les
Italia
nos
Zim
babw
ense
Gan
iens
es
Tanz
anos N
iger
iano
s
Polin
esio
sM
aorie
s
Saud
ies Etio
pes
Indú
es
Cub
anos
-Mes
tizos
Nic
arag
üens
es
Cin
gale
ses
de S
ri La
nka
Gan
iens
es
0,0
2,0
4,0
6,0
8,0
10,0
12,0
14,0
Populations
Perc
enta
ge (
%)
of d
ebri
soqu
ine
poor
met
abol
izer
s
Asians
White-Europeans
Mediterraneans
Black-Africans
Others
Polynesians
RED IBEROAMERICANA DE FARMACOGENETICA (CYTED.206RT0290) www.ribef.org
CEIBA Consorcio Europeo Ibero Americano Farmacogenética n=6479
GENOTYPING n= 5482 Phenotyping=2540 Ancestry= 3386
North America
México North Durango
México North Monterrey
México DF Center
México South Chiapas
Central America
Nicaragua
Costa Rica
Caribe
Cuba
Iberians
España, Extremadura
Portugal, Coimbra
South America Pacific
Colombia, Bogotá
Ecuador, Quito
Perú, Lima
Perú, Puno
South America Atlantic
Brasil
Chile
Uruguay, Montevideo
Argentina, B Aires
Argentina, Ashkenazy
CYP2C9
Population n CYP2C9 *1 CYP2C9 *2 CYP2C9 *3
Spanish 276 0.78 0.14 0.08
White-Americans 280 0.83 0.13 0.04 White-Americans 200 0.86 0.08 0.06 Swedish 860 0.82 0.11 0.07 British 200 0.79 0.13 0.09 Italians 314 0.80 0.11 0.09
Total caucasians 2444 0.80 0.12 0.08 Indo-europeans 1812 0.80 0.11 0.08 Africans 740 0.96 0.03 0.01
Asians *Mexican-Americans
2494 98
0.97 0.86
--- 0.08
0.03 0.06
CYP2C9 genetic polymorphism: Interethnical variability
*LLerena et al, 2005. The Pharmacogenomic Journal
Center for Pharmacogenomics and Clinical Pharmacology. UCLA, USA.
University of Extremadura, Spain
University of Beira Interior, Portugal
Center for Pharmacogenomics & Clinical Pharmacology
David Geffen School of Medicine. Neuropsychiatric Institute
RED IBEROAMERICANA DE FARMACOGENETICA
www.ribef.com CEIBA Consortium [email protected]
ENDOBIOTICS
PERSONALITY
NEUROCOGNITION
PSYCHOPATHOLOGY
Variability in therapeu>c response and adverse effects
An>depressants
-‐ SSRI Fluoxe>ne
-‐ TCA Clomipramine
An>psycho>cs
-‐ Haloperidol -‐ Risperidone
DIFFERENCES IN DRUG RESPONSE VARIABILITY IN PSYCHOPATHOLOGY
Catecholamines
-‐ Serotonine
-‐ Dopamine?
CYP2D6 Drugs and vulnerability to Psychopatology
serotonin
5-methoxytryptamine
Yu et al., 2003
CYP2D6
CYP2D6 and endogenous monoamines metabolism: serotonine
CYP2D6 and endogenous monoamines metabolism
(LLerena et al., 1993)
CYP2D6 activity and personality in a Cuban
population is replicated (Gonzalez et al., 2008):
Same results!
Psychic anxiety (PA)
22 24 26 28 30
EM1 EM2 EM3 PM Fenotipo hidroxilador debrisoquina
Med
ia P
untu
ació
n Te
st K
SP Psychasthenia (PS)
22
23
24
25
EM1 EM2 EM3 PM Fenotipo hidroxilador debrisoquina
Med
ia P
untu
ació
n Te
st K
SP
Inhibition of aggresion
24
26
28
EM1 EM2 EM3 PM Fenotipo hidroxilador debrisoquina
Med
ia P
untu
ació
n Te
st K
SP
Socialization (SO)
50 52 54 56 58
EM1 EM2 EM3 PM Fenotipo hidroxilador debrisoquina
Med
ia P
untu
ació
n Te
st K
SP
Spaniards Cubans
KSP Personality PM Cuba = Spain
CYP2D6 and personality: replica>on in Cubans
Suicide
University of Extremadura, Spain
Adrián Llerena [email protected]
Sixth cause of death
First Non-natural cause of death (higher than trafic accidents)
> Active genes in Eating Disorders
CYP2D6 and Eating Disorders (Peñas-Lledó et al., 2010)
University of Extremadura, Spain Eva M Peñas-LLedó PhD 2012
CYP2D6 URs and Eating Disorders Symptoms
(Peñas-Lledó et al. 2012 in press)
> Active genes among ED with history of Suicidal Behaviour
CYP2D6 and Suicidal Behaviour among Ea>ng Disorders (Peñas-‐Lledó et al., 2011)
University of Extremadura, Spain Eva M Peñas-LLedó PhD 2012
1. Implication of CYP2D6 in endogenous metabolism
2. Treatment failure with drugs metabolized by CYP2D6
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Rela>onship of CYP2D6 and suicide
University of Extremadura, Spain Eva M Peñas-LLedó PhD 2012
HYPOTHESIS
Clinical implications of CYP2D6 polymorphism and its relevance for the world global health.
• Pharmacogenetics might contribute to narrowing the “biotechnological gap”
between the developed and undeveloped world.
• This together with information from independent clinical studies may help to the
individualization of drug therapy in every place of the world.
RIFF - Adrián LLerena