Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 • 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; Drugs 2D6; 3A3, 3A4,5 1A1,1A2; 2A6; 1B; 2E1; Environment 3A3, 3A4,5 Genetic 1A; 2A6; 2C9,19; 2D6; Polymorphism 2E1 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 • • • • • • 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 • • • • • 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