WHAT ELSE DID I INHERIT?(GENETIC VARIATION IN DRUG METABOLISM

AMONGST VARIOUS ETHNIC GROUPS)

Annette Youssef Pharm D. Candidate 2010

June 25, 2009

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

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

SEGREGATION OF ETHNIC GROUPS

Country’s 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

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

US Census Data

Country 1990 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

United States

7.9 9.0 9.3 9.3 9.7 9.8 9.7 10.4 10.8 11.5 11.7 11.9 12.1 12.1

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.

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

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 1900’s

Founder Effect

Definition: when a population is established by a very small number of individuals from a larger population

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

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

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)

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)

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)

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

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

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

Data Presentation

Population N (# of Subjects) Fully Functional Loss of Function/Greatly Reduced PMID

CYP 2C9*1 CYP 2C9*2 CYP 2C9*3

African-American (Black)

66 0 0.008 16424822

100 0.985 0.01 0.005 17201743

Literature 0.985 0.01 0.0215 15229460

Literature 0.964 0.036 No Data 12406644

329 0.975 0.025 No Data 12406644

225 98 No Data 0.02 12406644

150 977 No Data 0.023 12406644

African (Black) 120 0.935 0.0435 0.0215 15229460

Ashekenazi Jew

100 No Data 0.085 0.08 16111713

250 0.772 0.14 0.086 18240905

Caucasian

115 No Data 0.143 0.109 16424822

Literature No Data 0.11 0.07 16082538

Literature No Data 0.08 0.06 16082538

Literature No Data 0.143 0.162 16082538

Literature 0.8085 0.115 0.0715 15229460

47 0.723 0.223 0.053 12621390

Data Presentation

2C19 Genotype Frequency Example:

3+ Functional Alleles

CYP2C19*1 Caucasian: 86%African: 81%Asian: 63%

Non-Functional Allele

CYP2C19*2 Caucasian: 13%African: 18%Asian: 30%

CYP2C19*3 Caucasian: 1%African: 1%Asian: 10%

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:

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

Thank You Everyone at Genelex!

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/founder.gif&imgrefurl=http://userpages.umbc.edu/~farabaug/biol100/overheads/lect17over.html&usg=__VmqH9W1glLR4SrvgDImcgFD6czg=&h=342&w=594&sz=7&hl=en&start=3&um=1&tbnid=nlYgKs5g2ZSoiM:&tbnh=78&tbnw=135&prev=/images%3Fq%3Dfounder%2Beffect%2B-%2Bpicture%26hl%3Den%26sa%3DX%26um%3D1

References (2C9)

16424822 16082538 12803577 12621390 12435384 12406644

17201743 15229460 12445031 12406644 10510154 16082538

15229460 12621390 17201743 12406644 15795654 15900281

12406644 12803577 17201743 12406644 16111713 15229460

12406644 17201743 17201743 12406644 17201743 15229460

12406644 12803577 11678789 12406644 17201743 12803577

12406644 12406644 15177309 12406644 17201743

15229460 12406644 16111713 11298075 12406644

16111713 12406644 9631918 16111713 12406644

18240905 12406644 16424822 16111713 12406644

16424822 12950145 17201743 12879168 12406644

16082538 12047484 17201743 11372590 12406644

16082538 11678789 12803577 9920790 12406644

References (2C19)

9732415

17201743 9797794 8873219 18240905

14616425

16815315 9797794 9435198 17201743

14616425

16815315 17201743 9103550 17201743

16815315

16815315 8807668 12879168 17201743

16815315

17201743 17201743 14583683 15177309

References (2D6)

9241659 8098046 12152006 11422605 8911874

9012401

9918137 8098046 9164697 10634133

1681816

10634130 8097442 11753272 11470994

7909282

11505219 10886115 10634134 11372584

7697944 9918137 10975611 10073750 8764380

9511177 11505219 10340923 7908586 10376769

9731721 17301689

References (3A7)

15903124