Post on 26-Mar-2015
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