WHAT ELSE DID I INHERIT GENETIC VARIATION IN DRUG METABOLISM AMONGST VARIOUS ETHNIC GROUPS

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WHAT ELSE DID I INHERIT?(GENETIC VARIATION IN
DRUG METABOLISM AMONGST VARIOUS ETHNIC GROUPS)
June 25, 2009

• Annette Youssef Pharm D. Candidate 2010

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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

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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

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SEGREGATION OF ETHNIC GROUPS

• Invisible Boundaries

• Others

• 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

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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

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US Census Data
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.
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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

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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 immigrantsespecially
  in the early 1900s

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Founder Effect

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

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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

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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

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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)

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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)

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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)

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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

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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

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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

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Data Presentation
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Data Presentation

• 2C19 Genotype Frequency Example

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Data Presentation

• 2C19 Phenotype Frequency Example

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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

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Thank You Everyone at Genelex!
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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?imgurlhttp//user
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References (2C9)
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References (2C19)
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References (2D6)
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References (3A7)