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ScienceWeek
PUBLIC HEALTH: RACE VS. GENES AS RISK FACTORS IN HEALTH
The following points are made by Mike Bamshad (J. Am. Med. Assoc. 2005 294:937):
1) An important goal of 21st-century medicine is to predict an individual's medical future -- that is, to identify the set of risk factors for disease and predictors of treatment response that influence a person's health, with the goal of more effectively treating and preventing disease. Throughout much of the world, race -- using its historical meaning as a descriptor of Africans, Asians, Europeans, Native Americans, and Pacific Islanders -- is often considered one key determinant of health.[1,2]
2) Race might influence an individual's health in several ways. It might covary with different environmental or genetic factors that underlie risk, different interactions between genetic and environmental factors, or different combinations thereof. Many environmental factors that influence health are known, but most of the genetic factors, much less interactions between the two, remain to be discovered. Nevertheless, there is widespread speculation that genetic factors influencing health differ among racial groups because many health-related traits vary among racial groups.[3] This speculation has revived a long-standing debate in medical and scientific communities about the validity and necessity of using race to make inferences about an individual's genetic ancestry, some scientists embracing this idea and others dismissing it.[4,5]
3) In this debate, one issue that is commonly confused is the difference between race and ancestry. Ancestry refers to objective genetic relationships between individuals and among populations, whereas race has always been a somewhat arbitrary definition of population boundaries. For example, while an individual might have ancestors from Europe, Africa, and North America, he or she still might be categorized as an African American. Therefore, race captures some biological information about ancestry, but it is not equivalent to ancestry.
4) Yet clinicians often want to know whether it is valid and reliable to use race as a proxy to infer an individual's genetic risk for disease and treatment response. Whether race matters is, however, complicated because it depends on the relationship between the genetic risk factor, ancestry, and race. For example, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors for hypertension treatment may not work as well, on average, in African Americans compared with European Americans, but both types of drugs appear to work perfectly well in a large fraction of African Americans and poorly in some European Americans.
5) The observation might be explained by a hypothetical genetic predictor of positive response to ACE inhibitors that is common in European Americans but that is also present in some African Americans because of admixture and absent in some European Americans. In such a case, the best predictor of treatment response might be the presence of the variant (ie, direct testing); the next best might be an accurate estimator of genetic ancestry, and race might be only a poor predictor of genetic risk and therefore treatment response.
References (abridged):
1. Osborne NG, Feit MD. The use of race in medical research. JAMA. 1992;267:275-279.
2. Oppenheimer G. Paradigm lost: race, ethnicity, and the search for a new population taxonomy. Am J Public Health. 2001;91:1049-1055.
3. Institute of Medicine. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC: National Academies Press; 2003
4. Risch N, Burchard E, Ziv E, Tang H. Categorization of humans in biomedical research: genes, race, and disease. Genome Biol. 2002;3:1-12
5. Burchard EG, Ziv E, Coyle N, et al. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med. 2003;348:1170-1175
J. Am. Med. Assoc. http://www.jama.com
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ANTHROPOLOGY: ON HUMANS AND RACE
The following points are made by D.A. Hughes et al (Current Biology 2004 14:R367):
1) Systematists have not defined a "type specimen" for humans, in contrast to other species. Recent attempts to provide a definition for our species, so-called "anatomically modern humans", have suffered from the embarrassment that exceptions to such definitions inevitably arise -- so are these exceptional people then not "human"? Anyway, in comparison with our closest-living relatives, chimpanzees, and in light of the fossil record, the following trends have been discerned in the evolution of modern humans: increase in brain size; decrease in skeletal robusticity; decrease in size of dentition; a shift to bipedal locomotion; a longer period of childhood growth and dependency; increase in lifespan; and increase in reliance on culture and technology.
2) The traditional classification of humans as Homo sapiens, with our very own separate family (Hominidae) goes back to Carolus Linnaeus (1707-1778). Recently, the controversial suggestion has been made of lumping humans and chimpanzees together into at least the same family, if not the same genus, based on the fact that they are 98-99% identical at the nucleotide sequence level. DNA sequence similarity is not the only basis for classification, however: it has also been proposed that, in a classification based on cognitive/mental abilities, humans would merit their own separate kingdom, the Psychozoa (which does have a nice ring to it).
3) As for sub-categories, or "races", of humans, in his Systema Naturae of 1758 Linnaeus recognized four principal geographic varieties or subspecies of humans: Americanus, Europaeus, Asiaticus, and Afer (Africans). He defined two other categories: Monstrosus, mostly hairy men with tails and other fanciful creatures, but also including some existing groups such as Patagonians; and Ferus, or "wild boys", thought to be raised by animals, but actually retarded or mentally ill children that had been abandoned by their parents. In his scheme of 1795, Johann Blumenbach (1752-1840) added a fifth category, Malay, including Polynesians, Melanesians and Australians.
4) Blumenbach is also responsible for using the term "Caucasian" to refer in general to Europeans, which he chose on the basis of physical appearance. He thought Europeans had the greatest physical beauty of all humans -- not surprising, as he was of course European himself -- and amongst Europeans he thought those from around Mount Caucasus the most beautiful. Hence, he named the "most beautiful race" of people after their supposedly most beautiful variety -- a good reason to avoid using the term "Caucasian" to refer to people of generic European origin (another is to avoid confusion with the specific meaning of "Caucasian", namely people from the Caucasus).
5) The extent to which racial classifications of humans reflect any underlying biological reality is highly controversial; proponents of racial classification schemes have been unable to agree on the number of races (proposals range from 3 to more than 100), let alone how specific populations should be classified, which would seem to greatly undermine the utility of any such racial classification. Moreover, the apparent goal of investigating human biological diversity is to ask how such diversity is patterned and how it came to be the way that it is, rather than how to classify populations into discrete "races".(1-4)
References:
1. Nature Encyclopedia of the Human Genome. (2003). Cooper, D. ed. (Nature Publishing Group),
2. Fowler, C.W. and Hobbs, L. (2003). Is humanity sustainable?. Proc. R. Soc. Lond. B. Biol. Sci. 270, 2579-2583
3. Encyclopedia of Human Evolution and Prehistory. (1988). Tattersall, I., Delson, E., and Van Couvering, J. eds. (Garland Publishing)
4. World Health Organization Website http://www.who.int
Current Biology http://www.current-biology.com
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PUBLIC HEALTH: ON RACE-BASED THERAPEUTICS
The following points are made by M. Gregg Bloche (New Engl. J. Med. 2004 351:2035):
1) Are we moving into a new era of race-based therapeutics? The recent publication of the African-American Heart Failure Trial (A-HeFT), a clinical trial of a medication intended for a single racial group, poses this awkward question. The study's most striking finding -- that the addition of isosorbide dinitrate and hydralazine to conventional therapy for heart failure reduced relative one-year mortality by 43 percent among blacks -- has provoked wide discussion. The trial's sponsor, NitroMed, which holds a patent on the fixed-dose combination of isosorbide dinitrate and hydralazine that was used, posits that heart failure has a different pathophysiology in blacks than in whites, necessitating different treatment strategies.(1)
2) The reported 43 percent relative decrease in the rate of death due to heart failure among blacks is cause for celebration. There is wide agreement that blacks die from heart failure at rates disproportionate to those among whites. But to assess A-HeFT's larger implications for the role of race in therapeutic design, it is important to be clear about what the study has not shown.
3) First, A-HeFT has not established that adding isosorbide dinitrate and hydralazine to conventional therapy for heart failure yields greater benefits for blacks than for other racial or ethnic groups. The study, which enrolled only self-identified blacks, did not test this hypothesis. The clinical and economic logic behind A-HeFT's design has its roots in previous, multiracial studies that compared isosorbide dinitrate and hydralazine with other investigational drugs, administered in combination with different conventional therapies. These therapies were standard in their day but are inferior to the conventional therapy used today, which typically includes an angiotensin-converting-enzyme (ACE) inhibitor. Indeed, one of these previous studies helped to establish ACE inhibitors as standard treatment. This trial compared isosorbide dinitrate and hydralazine with the ACE inhibitor enalapril and demonstrated that enalapril resulted in a greater overall reduction in mortality.(2)
4) An ill-defined subgroup of patients, though, did well when treated with isosorbide dinitrate and hydralazine and fared poorly with enalapril. Seizing on this opportunity, a biotechnology firm obtained intellectual-property rights to a fixed-dose combination of isosorbide dinitrate and hydralazine and sought approval from the Food and Drug Administration (FDA) in 1996 to market this formulation as a new drug. The FDA declined, citing statistical uncertainties in the trial data.(1) That is when race entered the picture. A group of investigators (including the holder of the patent on the combination treatment) reanalyzed the previous clinical-trial data according to race and concluded in 1999 that the combination treatment did as well as enalapril at prolonging the lives of black patients with heart failure.(3) Other work suggested that ACE inhibitors were less effective in blacks than in whites.
5) At this point, it might have made clinical and scientific sense to add isosorbide dinitrate and hydralazine to conventional therapy (which by now typically included an ACE inhibitor) and to compare this combination to conventional therapy alone -- for all patients with heart failure, regardless of race. Such a trial had not been performed, since the standard therapies used in earlier trials did not include ACE inhibitors. But race consciousness offered a faster way through the FDA's regulatory maze. In 1999, NitroMed obtained intellectual-property rights to fixed-dose isosorbide dinitrate and hydralazine and said it would seek FDA approval to market the formulation as a therapy for heart failure in blacks. Two years later, the FDA indicated to NitroMed that successful completion of a clinical trial in black patients with heart failure would probably result in approval.(1) This commitment gave rise to A-HeFT, and the publication of this trial's results virtually ensures FDA approval.
6) We need not shy away from the potential benefits of race-conscious therapeutics, but we should manage its downside risks. Greater awareness among physicians and the public that race is at best a placeholder for other predispositions, and not a biologic verity, would be a first step. Beyond such awareness, companies -- such as NitroMed -- that stand to gain from taking account of race could commit a substantial portion of their profits to research on genetic, psychosocial, and other mechanisms that might underlie racial gaps in clinical response.(3-5)
References (abridged):
1. Kahn J. How a drug becomes "ethnic": law, commerce, and the production of racial categories in medicine. Yale J Health Policy Law Ethics 2004;4:1-46
2. Cohn JN, Archibald DG, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310
3. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail 1999;5:178-187
4. Lifton RJ. The Nazi doctors: medical killing and the psychology of genocide. New York: Basic Books, 1986
5. Cacioppo JT, Hawkley LC. Social isolation and health, with an emphasis on underlying mechanisms. Perspect Biol Med 2003;46:Suppl:S39-S52
New Engl. J. Med. http://www.nejm.org
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