1. PHARMACOGENETICS, POPULATION STRUCTURE AND ADMIXTURE Guilherme Suarez-Kurtz Rio de Janeiro - Brazil Guilherme Suarez-Kurtz Rio de Janeiro - Brazil RS-ICSU-IAP 2006

2. Pharmacogenetics deals with drug responses (therapeutic or adverse) and their modification by hereditary factors.

3. 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

4. one drug/one dose fits all THE CURRENT PARADIGM

5. THE PHARMACOGENETICS PROMISE personalised therapy ”paradigm-disrupting”

6. 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.

7. DRUG ACTIVE/inactive metabolite Phase I Cytochrome P450 (CYP) DRUG and XENOBIOTIC METABOLISM Phase II Glutathione-S-transferases (GST) INACTIVE metabolite

9. Continental populations

10. Population stratification in Singapore Chowbay et al., 2005 0 10 20 30 40 50 60 70 GSTM1-null Frequency (%) Indian Chinese Malay CYP3A5*1

11. Stratification : subpopulations

12. Data from Park et al., 2000; Tetlow et al., 2004 0 20 40 60 Genotype frequency (%) *A/*A *A/*B *B/*B GSTM3(6bp deletion) African Bantu White American African-American

13. Data from Park et al., 2000; Medeiros et al., 2004; Suarez-Kurtz et al., 2006 0 20 40 60 Genotype frequency (%) *A/*A *A/*B *B/*B GSTM3(6bp deletion) African Bantu Portuguese Black Brazilians

14. Stratification : admixture

15. 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

16. 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 <

17. African ancestry index Brazilians in southeast rural area Parra et al., 2003 6% 38% 53%

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

19. African ancestry index Brazilians in southeast rural area Parra et al., 2003 6% 38% 53%

20. ADMIXTURE IN BRAZILIANS

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

22. European African Amerindian Self-declared WHITE Brazilians European African Amerindian Self-declared BLACK Brazilians Pena et al. 2006

23. 0.0 0.1 0.2 0.3 0.4 Genotype frequency GSTM3*B/*B White Black African ancestry (%) 75

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

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

27. Serre & Pääbo, 2004

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

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

31. Surui

32. 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, Tanzanian0.8-1.8 Ethiopian0 European0 Asian0

33. > G > Glu G/C

34. Suarez-Kurtz et al. Clin Pharm Ther, 2005 92% European 7.5% African 0.5% Amerindian mtDNA L3d

35. Father Mother

36. *5 *1 CYP2C9 alleles I W W I W “Race/ethnic” categorization/discrimination: appearance vs. descent