PHARMACOGENETICS, POPULATION STRUCTURE AND ADMIXTURE Guilherme Suarez-Kurtz Rio de Janeiro - Brazil Guilherme Suarez-Kurtz Rio 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 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) INACTIVE metabolite

Continental populations

Population stratification in Singapore Chowbay et al., GSTM1-null Frequency (%) Indian Chinese Malay CYP3A5*1

Stratification : subpopulations

Data from Park et al., 2000; Tetlow et al., Genotype frequency (%) *A/*A *A/*B *B/*B GSTM3(6bp deletion) African Bantu White American African-American

Data from Park et al., 2000; Medeiros et al., 2004; Suarez-Kurtz et al., Genotype frequency (%) *A/*A *A/*B *B/*B GSTM3(6bp deletion) African Bantu Portuguese Black 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 ~ 0.5 M Portuguese ~ 4.5 M immigrants Portugal 1.7 M Italy 1.6 M Spain 0.7 M Germany 0.25 M ~ 3.6 M Enslaved Africans Sources of the tri-hybrid Brazilian population Suarez-Kurtz <

African ancestry index Brazilians in southeast rural area Parra et al., % 38% 53%

African ancestry index Brazilians in southeast rural area Parra et al., 2003

African ancestry index Brazilians in southeast rural area Parra et al., % 38% 53%

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

Genotype frequency GSTM3*B/*B White Black African ancestry (%) 75

E. Parra et al., Nat Genet 2004 African-Caribbeans African-Americans Puerto Ricans Hispanics Mexicans *

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

Serre & Pääbo, 2004

African European Asian Oceanian Native American Serre & Pääbo, Genome Res 2004

Lamba et al. Clin Pharm Ther 2000 CYP2C19*2 CYP2C19*3 Worldwide gradients in CYP2C19 variant allele frequency

Surui

FREQUENCY DISTRIBUTION OF CYP2C9*5 Data from Dickman et al. (2001), Xie et al. (2003, and references therein), Llerena et al. (2004). PopulationCYP2C9*5 North-American African-American1.7 European-American0 Mexican-American0 African Beninese, Tanzanian Ethiopian0 European0 Asian0

> G > Glu G/C

Suarez-Kurtz et al. Clin Pharm Ther, % European 7.5% African 0.5% Amerindian mtDNA L3d

Father Mother

*5 *1 CYP2C9 alleles I W W I W “Race/ethnic” categorization/discrimination: appearance vs. descent