“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

allerena@unex.es

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

Major drug metabolizing enzymes

CYP2D6 CYP2C9

CYP2C19 CYP1A2

Adrián LLerena 2012 allerena@unex.es

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 allerena@unex.es

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 allerena@unex.es

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 allerena@unex.es

-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 allerena@unex.es

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 allerena@unex.es

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 allerena@unex.es

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

Para ver esta película, debedisponer de QuickTime™ y de

un descompresor .

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