Transcript UNDERSTANDING THE ROLE OF PHARMACOTHERAPY AND …

PHARMACOGENOMICS AND
RACE BASED MEDICINE
Jerome Wilson, M.A., Ph.D.
10th Biennial Symposium on Minorities, The
Medically Underserved & Cancer
Omni Shoreham Hotel
April 20, 2006
Washington, DC
PHARMACOGENOMICS
• The science which aims to define the
genetic determinants of drug effects
RACE MEDICINE
• How has it been used?
• Has race based medicine contributed to
the current state of health disparities in the
United States?
• Will the elimination of race based medicine
improve the health of minorities and the
society at large?
U.S. Census Racial Categories, 1790-2000
•
1790
Free White Males; White Females; All Other
Persons; SLAVES
•
1820
Free White Males; Free White Females; Free
Colored Persons; All Other Persons except
Indians Not Taxed; SLAVES
•
1840
Free White Persons; Free Colored Persons;
SLAVES
•
1880
White; Black; Mulatto; Chinese; Indian
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1920
•
1960
White; Black; Mulatto; Indian; Chinese;
Japanese; Filipino; Hindu; Korean; Other
(plus write in)
White; Negro; American Indian; Japanese;
Chinese; Filipino; Hawaiian; Korean; other
(print race)
U.S. Census Racial Categories, 1790-2000 (continues)
•
1980
White; Negro or Black; Japanese; Chinese;
Filipino; Korean; Vietnamese; American Indian;
Asian Indian; Hawaiian; Guamanian; other Asian
Pacific Islander;Other Race
•
1990
White; Black or Negro; American Indian; Eskimo;
Aleut; Chinese; Filipino; Hawaiian; Korean;
Vietnamese; Japanese, Asian Indian;
Samoan; Guamanian; Other Asian Pacific
Islander; Other
•
2000
White; Black or African American; American
Indian or Alaska Native; Asian Indian; Chinese;
Filipino; Japanese; Korean; Vietnamese; Native
Hawaiian;Guamanian or Chamorro; Samoan;Other Asian;
Other Pacific Islander; Some other race (print race)
RACE BASED MEDICINE
VS
GENETIC VARIATION
“Racial and ethnic groups
compromise important
subpopulations whose special
needs and drug responses
traditionally have been undervalued
and/or ignored”
Source: National Pharmaceutical Council and National Medical
Association, 2002
Racial categorization in Medicine
• Superficial physical characteristics commonly
associated with racial groups: skin color, hair
type and color, facial features, etc.
• These characteristics have little or no relevance
to drug response
• Genetically determined differences in response
to drugs exist among individuals and populations
•
Source: Burroughs, Maxey and Levy, 2002
The Human Genome Project
**
Leading the revolution in biotechnology
**
Promises to change current strategies for
- drug development, clinical trials and
the practice of medicine
- understanding human similarities ad
differences by informing issues
surrounding
- race
- ethnicity
- identity
- ancestry
- admixture
Genomic Science and Health Disparity
Can Genetics Explain Health Disparity?
Is there such a thing as
An African gene?
A Caucasian gene?
An Asian gene?
OR
Are we dealing with differential frequency of
susceptibility/resistance genes?
Source: Dr. Charles Rotimi, National Human Genome Center at
Howard University
What is My Race?
Race Categories:
• African American (F)
DNA Analysis:
West African 58%
European
39%
Native American 3%
• White (M)
European
North African
• African American (F)
West African
British Isles
Middle EasternNorth African
80%
11%
83%
10%
7%
Geography Not Race
• Should geographic structure of genetic
variation be considered during drug
evaluation --Yes.
• Are racial labels sufficient to represent the
geographic variation that is present?
– No.
– In the context of drug trials, there appears little
justification for favouring racial labels over
explicit genetic inference
Race-based Pharmacotherapy
• The mixed heritage of most Americans
makes skin color a dangerous basis for
treating patients.
• “Race-based medicine would probably kill
more people that would cure”-Professor
Jonathan Marks
Factors that are Important
Determinants of Intersubject Variability
• Demographic: Age, Body Weight or Surface
Area, Gender, “Race”, Ethnic Background
• Genetic: CYP2D6, CYP2C19
• Environmental: Smoking, Diet
• Physiological/Pathophysiological: Renal
(creatinine Clearance) or Hepatic impairment,
Disease State
• Concomitant Drugs: Prescription and OTC
• Other Factors: Meals, Circadian Variation,
Formulations
Drug Metabolism
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes
(oxidation, conjugation)
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
Factors Influencing Activity and Level of CYP Enzymes
Nutrition
1A1;1A2;2E1; 3A3; 3A4,5
Smoking
1A1;1A2
Alcohol
2E1
1A1,1A2; 2A6; 2B6; 2C;
2D6; 3A3, 3A4,5
1A1,1A2; 2A6; 1B; 2E1;
Environment
3A3, 3A4,5
Genetic
1A; 2A6; 2C9,19; 2D6;
Polymorphism 2E1
Drugs
Red indicates enzymes important in drug metabolism
S. Rendic & F. J. Di Carlo Drug Metab Rev 29: 413-580, 1997
CYP2D6
• Painkillers: Codeine, OxyContin, Percocet,
Ultram, Ultracet, Vicodin
• Antidepressants: Effexor, elavil, Paxil,
Prozac, Imipramine
• Cardiovascular: Coreg, Inderal, Lopressor,
Timoptic, Toprol
• Miscellaneous: Claritin, dextromethorphan
(active ingredient in most
cough suppressants), Flomax
CYP2C19
• Painkillers: methadone
• Antidepressants: Anafranil, Celexa,
imipramine, Prozac,
Zoloft
• Cardiovascular: Inderal
• Protein pump inhibitors: Prevacid,Prilosec
• Miscellaneous: Dilantin, Valium
UDP Glucuronyl Transferase
1A1
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Responsible for Gilbert’s Bilirubinemia
absent in ~15% of Caucasians
< 5% Asians
> 50% of Africans
> 50% of Hispanics
Decreased activity in hypoglycemic and
malnourished conditions, so Gilbert’s
hyperbilirubinemia is “revealed” by these
conditions.
N-Acetylation Polymorphism
NAT-2
• Late 1940’s : Peripheral Neuropathy noted
in patients treated for tuberculosis.
• 1959 : Genetic factors influencing
isoniazid blood levels in humans. Trans
Conf Chemother Tuberc 1959: 8, 52–56.
Incidence of the Slow Acetylator NAT-2
phenotype
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50% among Caucasians
50% among Africans
20% among Egyptians
15% among Chinese
10% among Japanese
Hierarchy of Pharmacogenetic Information from
Single Nucleotide Polymorphisms (SNPs)
SNPs that change clinical outcome
SNPs that change drug response
SNPs that change pharmacokinetics
SNPs that change activity in vitro
Non-conservative amino acid changes
Non-synonymous SNPs in exons
Exon-based changes
All SNPs
Hierarchy of Pharmacogenetic Information from
Single Nucleotide Polymorphisms (SNPs)
SNPs that change clinical outcome
SNPs that change drug response
SNPs that change pharmacokinetics
SNPs that change activity in vitro
Non-conservative amino acid changes
Non-synonymous SNPs in exons
Exon-based changes
All SNPs
How BiDil Became a Drug for
African Americans
• Developed in the early 1980s as a drug for
all Americans
• Reinvention of BiDil as a drug for African
Americans was driven by market
incentives
• FDA’s approval of BiDil as a drug for
African Americans endorses the use of
race as a biological category
FDA’s Approval of BiDil
• BiDil should have been approved under
the condition that further research be
conducted to find the markers that have
the actual functional association with drug
responsiveness
• Thus assuring that the drug be approved
for everyone with those markers,
independent of their “race”
Dangers of Media Simplifying
Clinical Research (1)
• “ 29 medicines (or combinations of
medicines) have been claimed, in peerreviewed scientific or medical journals, to
have differences in either safety or, more
commonly efficacy among racial or ethnic
groups. But these claims are universally
controversial, and there is no consensus
on how important race or ethnicity is in
determining drug response” – Nature Genetics,
2004
Dangers of Media Simplifying
Clinical Research (2)
• “[A] report in the journal Nature Genetics
last month [that] listed 29 drugs that are
known to have different efficacies in the
two races” – Los Angles Times, 2004
• By one count, some 29 medicines show
evidence of being safer or more effective
in one racial group or another, suggest
that more targeted medicines may be
coming.” – New York Times, 2004
How different must the response be
to get a “race drug”?
• Ace Inhibitors
• Less responsive in African
Americans than in Caucasians
• Beta Blockers
• More effective in Caucasians
than in African Americans
• Alpha Blockers
• More effective in Caucasians
that in African Americans
• Thiazide (diuretic)
• More effective in African
Americans than in Caucasians
Nat. Genet. Suppl., S36-S37 (2004)
Ethical and Legal Issues
Within Pharmacogenetics
• Risk of Loss of Patient Confidentiality
– Need for anonymized DNA storage systems
• Risk that existing patents will stifle
progress
– Need for careful interpration of Bayh-Dole
• Untangling the relationship between
genetics and self-described ethnicity
Lessons Learned
• The environment can mimic genetic
effects convincingly: tests of phenotype
will always be important
 Genetics is not everything, so every
genetic association must be examined for
potential “environmental” confounders