PHARMACOGENOMICS AND RACE BASED MEDICINE

Jerome Wilson, M.A., Ph.D.10th Biennial Symposium on Minorities, The

Medically Underserved & CancerOmni Shoreham Hotel

April 20, 2006Washington, 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 OtherPersons; SLAVES

• 1820 Free White Males; Free White Females; FreeColored Persons; All Other Persons except

Indians Not Taxed; SLAVES

• 1840 Free White Persons; Free Colored Persons;SLAVES

• 1880 White; Black; Mulatto; Chinese; Indian

• 1920 White; Black; Mulatto; Indian; Chinese; Japanese; Filipino; Hindu; Korean; Other

(plus write in)• 1960 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 MEDICINEVS

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

** 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

The Human Genome Project

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)

• White (M)

• African American (F)

DNA Analysis: West African 58%

European 39% Native American 3%

European 80% North African 11%

West African 83%British Isles 10%Middle Eastern- 7%North African

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

Hepatic microsomal enzymes (oxidation, conjugation)

Extrahepatic microsomal enzymesExtrahepatic microsomal enzymes (oxidation, conjugation)(oxidation, conjugation)

Hepatic non-microsomal enzymesHepatic non-microsomal enzymes (acetylation, sulfation,GSH, (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase,alcohol/aldehyde dehydrogenase,hydrolysis, ox/red)hydrolysis, ox/red)

Factors Influencing Activity and Level of CYP Enzymes

S. Rendic & F. J. Di Carlo Drug Metab Rev 29: 413-580, 1997

Nutrition 1A1;1A2;2E1; 3A3; 3A4,5

Smoking 1A1;1A2

Alcohol 2E1

Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5

Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5

Genetic Polymorphism

1A; 2A6; 2C9,19; 2D6; 2E1

Red indicates enzymes important in drug metabolism

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

• 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 PolymorphismNAT-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

• 50% among Caucasians

• 50% among Africans

• 20% among Egyptians

• 15% among Chinese

• 10% among Japanese

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

Hierarchy of Pharmacogenetic Information from Single Nucleotide Polymorphisms (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 peer-reviewed 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

• Beta Blockers

• Alpha Blockers

• Thiazide (diuretic)

Nat. Genet. Suppl., S36-S37 (2004)

• Less responsive in African Americans than in Caucasians

• More effective in Caucasians than in African Americans

• More effective in Caucasians that in African Americans

• More effective in African Americans than in Caucasians

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