1. WHAT ELSE DID I INHERIT? (GENETIC VARIATION IN DRUG METABOLISM AMONGST VARIOUS ETHNIC GROUPS) Annette Youssef Pharm D. Candidate 2010 June 25, 2009

2. Outline Project Proposal US Census Information The Founder Effect Niche in GeneMedRx Data Collection Methods Genotype Phenotype Calculations Data Presentation Significant Ethnic Variations in Drug Metabolism

3. Project Proposal Compile data on frequency of genetic variation in drug metabolizing enzymes in individual ethnic groups Predict varying degrees of drug metabolism amongst individual ethnic groups by converting genotype information into phenotype information Input this information into GeneMedRx Create Drug-Ethnic Group interaction Make Available to healthcare providers and patients

4. SEGREGATION OF ETHNIC GROUPS Countrys Borders Cultural Boundaries Language Religion Child Rearing Social Network: Work & School Settlement Economical Reasons: Endogamy & Cousin Couples: Contain land and property in the family Popular saying amongst Middle Eastern and Mediterranean cultures: The girl is for her cousin Limited Mobility Rising Gas Prices Government Policies: Embargos Xenophobia Invisible Boundaries Others

5. MERGING OF ETHNIC GROUPS Merging Borders: The European Union Migration United States Termed: The Melting Pot Technology Rapid Travel Rapid Communication: Internet, Satellite, Telephone Global Market Travel Business School: Study Abroad Military Leisure Acceptance of Other Cultures International Cuisine Alternative Therapies: Yoga, Acupuncture, Cupping

6. US Census Data Country 19901994199519961997199819992000200120022003200420052006 United States 7.99.09.3 9.79.89.710.410.811.511.711.912.1 United States: Foreign born as a percentage of the total population, 1990 and 1994 to 2006 *The 1994 to 2005 estimates presented in this table were derived from the US Census Bureau Current Population Survey (CPS). The 1990 & 200 data were derived from the 1990 & 2000 US Census of Population and Housing.

7. US CENSUS DATA 2000 RACE % One race........………......….........97.6 White........... …… ……….…...63.1 Hispanic/Latino.....................................12.5 Mexican......... ……...........................7.3 Puerto Rican.........................................1.2 Cuban............ ……......................0.4 Other Hispanic/Latino ………….…......3.6 Black/African American …………..…10.8 Native American/Alaska……………...0.8 Asian............. …………….…..3.2 Asian Indian............. …….. …0.5 Chinese................. ….....…..0.8 Filipino.................. …...… 0.6 Japanese.................. …. …..0.3 Korean.................. ……....0.4 Vietnamese................ ……....0.4 Other Asian 1............. …......0.4 Native Hawaiian/Pacific Islander. …..0.1 Native Hawaiian........... ….... - Guamanian or Chamorro.... ….. … - Samoan.................. …...... - Other Pacific Islander 2..... …… - Some other race......... …….…...4.8 Two or more races....... …........2.4

8. US Census Data Although ~10% of the US population was foreign born in 2000, only 2.4% of the US population had a mixed racial background The melting pot may not be an accurate description of the US Refers to the predicted homogeneity that would result from the influx of immigrants especially in the early 1900s

9. Founder Effect Definition: when a population is established by a very small number of individuals from a larger population

10. Founder Effect Results: In loss of genetic variation Subpopulation is genetically and phenotypically different from the larger population Thought to lead to speciation in extreme cases Genetic diversity amongst ethnic groups is a watered down version of the Founder Effect

11. NICHE IN GENEMEDRX Patient Histories: Record: Race/ethnicity already included in patient information sheets Current Use: Retrospective Medical Statistics Patient Identification Current Use: Prospective (minimally) Hypertension in Black Patients: Calcium Channel Blockers & Diuretics vs. ACE-I or Beta Blockers Crestor (rosuvastatin) in Asians: Greater degree of rhabdomylosis; choose different statin Use in GeneMedRx: Prospective Drug-Ethnic Background Interaction

12. NICHE IN GENEMEDRX Drug-Ethnic Background Interaction Display: Frequency of phenotype expression of drug metabolizing enzyme in a chosen ethnic group Display: Will Interact with the metabolism information for a certain drug Information Utilization: When frequency of variation in drug metabolism is high: Begin with a different dose (GeneMedRx Program) Choose alternative drug (GeneMedRx Program) Order a genetic test (Genelex)

13. GeneMedRx Now and After GeneMedRx Now: Can only predict a drug-gene interaction if someone has previously been genetically tested Predicts drug-drug interactions: other programs which already do this (Clinical Pharmacology)

14. GeneMedRx Now and After GeneMedRx After: Increase awareness of genetic variation Increase subscription to GeneMedRx: help recommend drug therapy in different ethnic groups May increase likelihood of ordering a genetic test Intelligent Genetic Testing: Prescriber can recommend genetic testing when appropriate Insurance Companies: Increase likelihood of paying for a genetic test if circumstances are appropriate To avoid cost of hospitalization due to adverse effects (Active Drug) To avoid cost of drug that is not effective (Prodrug)

15. DATA COLLECTION PubMed Search: Kew Words: Allele, Frequency, Genetic, Polymorphisms, Metabolism, Ethnic, Racial, CYP___, Variation Data Selection: All abstracts and full text articles that had genotype or allelic frequency data on particular cytochrome metabolizing enzyme of interest

16. Allele Frequency Genotype Phenotype Poor Metabolizer (1 Condition): Loss of function allele x loss of function allele Intermediate Metabolizer (3 Conditions): Reduced function allele x loss of function allele Functional allele x loss of function allele Reduced function allele x reduced function allele Extensive Metabolizer (2 Conditions): Reduced function allele x fully functional allele Fully functional allele x fully functional allele Ultra Rapid Metabolizer (2 Conditions): 3 or more copies of functional alleles 1 or more copies of alleles associated with tighter binding of substrate than fully functional allele

17. Alleles Loss of Function: Little or no ability to metabolize a substrate (drug and/or metabolite) Reduced Function: Decrease in the ability to metabolize substrate (drug and/or metabolite) ~50-70% Fully Functional: Full capability to metabolize a substrate

18. Data Presentation PopulationN (# of Subjects)Fully FunctionalLoss of Function/Greatly ReducedPMID CYP 2C9*1CYP 2C9*2CYP 2C9*3 African-American (Black) 6600.00816424822 1000.9850.010.00517201743 Literature0.9850.010.021515229460 Literature0.9640.036No Data12406644 3290.9750.025No Data12406644 22598No Data0.0212406644 150977No Data0.02312406644 African (Black)1200.9350.04350.021515229460 Ashekenazi Jew 100No Data0.0850.0816111713 2500.7720.140.08618240905 Caucasian 115No Data0.1430.10916424822 LiteratureNo Data0.110.0716082538 LiteratureNo Data0.080.0616082538 LiteratureNo Data0.1430.16216082538 Literature0.80850.1150.071515229460 470.7230.2230.05312621390

19. Data Presentation 2C19 Genotype Frequency Example: 3+ Functional Alleles CYP2C19*1Caucasian: 86% African: 81% Asian: 63% Non-Functional Allele CYP2C19*2Caucasian: 13% African: 18% Asian: 30% CYP2C19*3Caucasian: 1% African: 1% Asian: 10%

20. Data Presentation Ultra Rapid Metabolizer No Data Extensive Metabolizer Caucasian: 74% African: 66% Asian: 40% Intermediate Metabolizer Caucasian: 12% African: 15% Asian: 25% Poor Metabolizer Caucasian: 2% African: 4% Asian: 16% 2C19 Phenotype Frequency Example:

21. Significant Ethnic Variations in Drug Metabolism 2D6: ~25% of all ethnic groups are intermediate metabolizers of 2D6 substrates 2C9: ~6% of Caucasians are poor metabolizers of 2C9 substrates 2C19: ~16% of Asians are 2C19 poor metabolizers 2B6: ~7-14% of African Americans are poor metabolizers of 2B6 substrates 2E1: ~30-40% Asians are 2E1 poor metabolizers

22. Thank You Everyone at Genelex!

23. References Provine, W.B. 2004. "Ernst Mayr: Genetics and Speciation" Genetics 167: 1041-1046 http://www.census.gov/prod/2002pubs/p23-206.pdf http://images.google.com/imgres?imgurl=http://userpages.umbc.edu/~farabaug/biol100/overheads/fou nder.gif&imgrefurl=http://userpages.umbc.edu/~farabaug/biol100/overheads/lect17over.html&usg=__V mqH9W1glLR4SrvgDImcgFD6czg=&h=342&w=594&sz=7&hl=en&start=3&um=1&tbnid=nlYgKs5g2ZSoi M:&tbnh=78&tbnw=135&prev=/images%3Fq%3Dfounder%2Beffect%2B- %2Bpicture%26hl%3Den%26sa%3DX%26um%3D1

24. References (2C9) 16424822 1608253812803577126213901243538412406644 17201743 1522946012445031124066441051015416082538 15229460 1262139017201743124066441579565415900281 12406644 1280357717201743124066441611171315229460 12406644 17201743 124066441720174315229460 12406644 1280357711678789124066441720174312803577 12406644 151773091240664417201743 15229460 12406644161117131129807512406644 16111713 1240664496319181611171312406644 18240905 12406644164248221611171312406644 16424822 12950145172017431287916812406644 16082538 12047484172017431137259012406644 16082538 1167878912803577992079012406644

25. References (2C19) 9732415 1720174397977948873219 18240905 14616425 1681531597977949435198 17201743 14616425 1681531517201743 9103550 17201743 16815315 8807668 12879168 17201743 16815315 17201743 14583683 15177309

26. References (2D6) 9241659 809804612152006114226058911874 9012401 99181378098046916469710634133 1681816 1063413080974421175327211470994 7909282 11505219108861151063413411372584 7697944 991813710975611100737508764380 95111771150521910340923790858610376769 973172117301689

27. References (3A7) 15903124