PHARMACOGENETICS, POPULATION STRUCTURE AND ADMIXTURE

1. PHARMACOGENETICS, POPULATION STRUCTURE AND ADMIXTURE 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. O M P H A R M A C O G E N E T I C S O M P H A R M A C O G E N I C S Pharmacogenomics is pharmacogenetics with two SNPs

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

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 Cytochrome P450 (CYP) Phase I Glutathione-S-transferases (GST) Phase II INACTIVE metabolite DRUG and XENOBIOTIC METABOLISM

9. Continental populations

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

11. Stratification: subpopulations

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

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

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. Sources of the tri-hybrid Brazilian population 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 Suarez-Kurtz < 1551 - 1880 ~ 3.6 M Enslaved Africans

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

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

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

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

23. GSTM3*B/*B 0.4 0.3 Genotype frequency 0.2 0.1 0.0 < 25 25 - 50 50 -75 >75 White Black African ancestry (%)

24. African-Caribbeans African-Americans Puerto Ricans Hispanics Mexicans * E. Parra et al., Nat Genet2004

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

26. 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. CYP2C19*2 CYP2C19*3 Lamba et al. Clin Pharm Ther2000 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).

33. > G > Glu G/C

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

35. Mother Father

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