Correspondence: Dr RS Cooper, Department of Preventive Medicine and Epidemiology, Loyola University Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153, USA. E-mail: rcooper{at}lumc.edu
Accepted 17 October 2002
Technological advances that make it possible to identify nucleotide variants on a large scale are having an enormous impact on many fields in biology. This incursion of genetics is even being felt in the previously remote fields of epidemiology and public health. Yet while measuring the molecular basis of genetic variation will undoubtedly alter our understanding of the biological world, the implications for public health are much less clear. One of the most contentious areas involves the role of genetics in shaping health patterns among populations. In the pre-genomic era race was the surrogate for genetic effects at the population level, and it must follow that molecular research will now largely transform that agenda. Although we are at the earliest stages several critical issues have already emerged, and a burgeoning literature exists in both epidemiology and genetics on the application of the new molecular technology to the study of race and health. While many new and unexpected findings have begun to emerge, there is also tension between constraints which tend to keep this advancing field within the existing assumptions and the impulse to re-examine prior assumptions as empirical data lead us in unexpected directions.
The intersection of race, genes, and health maps an enormous territory and the comments here will by necessity be very selective. To begin with, there is the perpetually troublesome concept of race itself. A clear example of the tension between reaffirmation of tradition and transformation of biological concepts can be seen in the discussion on the value of race as a tool to categorize humans.15 Relying on a variety of sources of molecular evidence, some investigators now argue that an old ideahumans can be grouped into continental raceshas taken on new significance in public health and medicine.1 The basis for this conclusion appears to rest on evidence that genetic differentiation is greatest when defined on a continental basis and that multiple studies demonstrate that individuals from these groups can be clustered using molecular markers.
The central message put forward by those championing this updated version of race, wherein molecular data indeed show that genetic variation is discontinuous, represents a minority position, however. Templeton, for example, uses molecular to arrive at a very different conclusion:
Human races are not distinct lineages, and this is not due to recent admixture; human races are not and never were pure. Instead, human evolution has been and is characterized by many locally differentiated populations coexisting at any given time, but with sufficient genetic contact to make all of humanity a single lineage sharing a common evolutionary fate.2
Templeton also argues persuasively that some criteria (presumably a minimum value of Fst, or the proportion of genetic variance between as compared to within populations), is required to define a race or sub-species, and that all geographical arrangements are arbitrary. Although he did not reason from molecular evidence, Darwin came to the same conclusion on race:
Every naturalist who has had the misfortune to undertake the description of a group of highly varying organismshas encountered cases precisely like that of man; and if of a cautious disposition, he will end by uniting all the forms which graduate into each other ... ; for he will say to himself that he has no right to give names to objects which he cannot define.3
It is even far from clear that the important questions have been asked, or adequately tested thus far. First, one might wonder, why do we even want to know if races exist? Is this some sort of historical relic from the age when classification was the main object of nature science? But in reality we have passed those questions and must respond to the current agenda. To determine if broad racial groups exist, rather than asking, Can geographically distant groups be clustered?, it would seem more relevant to examine whether the global distribution of genetic variation can be divided into categories that correspond to continents. Addressing that question in 32 populations Romualdiet al. also come to the opposite conclusion: ... (T)here is little evidence, if any, of a clear subdivision of humans into biologically defined groups.4 Of course, the individual data set as well as the analysis used by Romualdi et al. is subject to criticism, and they are likely to be quickly superseded by a much larger project. But in the end much of this debate seems to hang on the interpretation of phrases like little evidence and correctly classify, and even if we accept some group-level genetic difference and some degree of clustering that by itself provides little help in determining whether races exist. Darwins caution still applieswhat is missing is a coherent construct. However one chooses to interpret the data it is hard to see how a correct estimate for the number of human races, or the designation of what those races are, can be obtained without a definition. It is perhaps characteristic of the concept of race that it has retained its vitality in the scientific literature during the molecular age while being excluded from the requirement of a definition that meets the usual statistical requirements in epidemiology. From the point of view of the population genetics it is hard to see how progress will be made until this issue is resolved.
On the other hand, there is a contrary view that race has little or no biological meaning.5,6 Unless qualified, however, these views can be taken as inconsistent with the evidence, and have been an irritant to geneticists who see the importance of population variation in an array of conditions. One of the crucial distinctions in this debate relates to the size of the population being considered. Geographically localized populations clearly have different frequencies for many disease-related genetic variants. The primary point of contention, however, lies in whether it is useful to consider continental populations as the most informative unit, or whether the descriptive value lies in groupings of the size of Corsicans, Scandinavians or Yorubans. Like most other measures of human variation, population size is obviously quantitative. Nonetheless, it has been well established that population of origin does provide useful information about the distribution of a number of genetic conditions. As suggested above by Romualdi et al., however, the relationship between populations and prevalent genetic conditions correlates poorly with continental race. Fortunately this controversy at least is amenable to empirical study and a numerical solution should be forthcoming, while opinions will continue to diverge about the importance of the result.
In the absence of a statistical definition, however, one might ask, How does race matter in public health or medicine?For continental race to have important biological meaning it must been shown to influence the broad public health patterns. This line of argument leads to a second crucial distinction inthe racehealth controversythe nature of the conditions being examined. Most known genetic variants that are disease-associated are random mutations in sub-populations or result from specific regional selection; these are clearly not racial traits, in the continental sense. This result occurs because most monogenic disorders are caused by mutations of recent origin and they are therefore restricted to a smaller breeding population than represented by continents. Whether either regional selection or random mutations account for susceptibility to the traits that underlie common disease, to which the entire species is susceptible in varying degrees (e.g. regulation of body fat stores, maintenance of salt, water and blood pressure homeostasis, DNA repair, etc.), is unproven.
Acknowledging that one could define chronic disease in a variety of ways, the racial patterns of the principal chronic conditions of public health interest are summarized in the Table. Despite widespread belief to the contrary, there is as yet no evidence that this pattern is shaped to any substantial degree by genetics. As acknowledged by even those in favour of thebiological importance of race, few genes underlying susceptibility to common diseases have been identified. One wonders, how, then, can one know that racial differences in common disease are genetic if one does not know what those susceptibility factors are? While there are many diseases with well-documented predisposing genes that vary among populations, they do not include complex chronic diseases.
In fact there are still enormous gaps in our understanding of the mechanism by which genetic variation influences physiological traits, like blood pressure, and associated common complex conditions, like hypertension. At the most basic level it should be pointed out that mutations that underlie essentially all monogenic disorders lead to altered (i.e. defective) proteins. These mutations are known as coding single nucleotide polymorphisms, or cSNP. Large scale genomic surveys have documented that cSNP are rare. Rare SNP are also of recent origin and, since they occurred after the original African diaspora, vary among population groups.7 Some observers have argued that a genetic basis for racial differences is plausible since cSNP are rare, and therefore vary among groups.1. However, while cSNP are the most likely candidates for variants affecting quantitative traits, that has not been widely demonstrated and the role of non-transcribed regulatory elements is still inadequately understood. It is well documented that quantitative traits in Drosophila, and less clearly in humans, are associated with common sequence variants in non-coding regions,811 althoughthe meaning of this result is obviously still obscure. In fact, many observers think it likely that common variants underlie susceptibility to common disease, and since these diseases are observed worldwide, these alleles will be pan-ethnic. Defining these mechanisms will require much deeper knowledge about genetic effects on common disease. Clearly an understanding of molecular mechanisms would also inform studies of racial/ethnic variation in disease. Persisting in efforts to fit our current notions of racial susceptibility onto the limited evidence we have to date is unlikely to be very helpful, however.
Like all dramatic new technologies, genomics is promoted with substantial hype. In some quarters the molecular revolution even seems to have resulted in a hurriedly arranged truce between genetics and public health.12,13 Both sides have put down their weapons and run across no-mans land to fraternize and celebrate. But some of this jubilation may be premature; at the very least the declarations of a blissful future of mutual benefit are extreme. Up till now medical genetics has confined itself to rare diseases and diagnostic testing.12,13 Whether there is an important role for molecular genetics in diseases of public health significance is far from certain, and if race is the surrogate for genes we have even bigger problems. In contradistinction to ethnic or geographical sub-populations, continental race matters in public health precisely because it is associated with enormous variation in common diseases. But to conclude that we already know that there is a genetic dimension to race that matters because it confers susceptibility to the common chronic diseases is premature. The competing hypothesis, in support of which we have enormous evidence, is that this variation results from differences in environmental exposures. While geneticists rightly object to statements that no biological differences exist among populations, to rush to the opposite extreme and advance claims about the genetic underpinningsof chronic diseases having emerged under conditions of the modern industrial lifestyle is equally unhelpful.
The details of the technical arguments are ultimately not the greatest source of concern in this debate. As genomics entersthe realm of public health, not only will changes be required inthe study design and the inferences that follow, but the nature of the discourse surrounding those inferences must also change.12,13 To argue that the existence of the races of man has been confirmed because of cluster analysis and description of superficial physical differences represents an intervention into public health that remains inadequately justified. Molecular data confers important analytical power, but it does not give population geneticists special authority to ignore historical context. Race is and always has been in essence a social construct. And I do not mean that some race effects are a result of social forces, but rather that the meaning of the word race is defined by its use. The construct of race simplifies and exaggerates the role of heritable factors.14 For geneticists to rush into this battleground, proclaiming to have verified by statistical analysis the popular wisdom that races exist is an inauspicious beginning to the molecular revolution in public health. This is not a question of hiding unhappy truths, but rather using scientific ideas for their social purpose.
Having argued that we should maintain an open mind in order to make use of what is new and unanticipated in the emerging molecular data, and that strong conclusions are at best premature, let me offer my own (tentative) conclusions. The concept of race is unlikely to have value in public healthnot only do the useful population units occur at a smallersize, race drags with it the dead weight of its noxious past. Populations will vary in the nature of their genetic risk profile, but this is unlikely to be true to any important degree for the common complex conditions. On that score we are muchmore alike rather than different. It will at any rate be a long time before we can test whether genes contribute much if anything to the observed public health disparities among demographic groups, however defined.
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