Two studies in this issue address ethnic differences in disease-related traits. Woo and colleagues [1] tested the hypothesis that Chinese persons may not have some of the detrimental effects of cigarette smoking on the coronary and peripheral vascular systems, in part because of greater protection against loss of endothelial function. Wall and associates [2] investigated the effect of a common aldehyde dehydrogenase gene variant that is specific to Asian persons on the rate of blood alcohol and acetaldehyde metabolism. These physiologic features invite questions about the nature of racial or ethnic differences in relation to the prevalence of disease or disease-related traits. Is race a biologically tenable concept? What is the extent of genetic differentiation in human populations? How has our understanding of the medical importance of ethnic differences been affected by the concept of race? Is it appropriate to consider ethnicity as a factor in treatment decisions?

Endothelium-dependent dilatation is much reduced in persons who are exposed to vascular disease risk factors, such as cigarette smoking [3], type 1 diabetes, hypercholesterolemia, and homocystinuria. Despite the high rate of cigarette smoking in China (about 70%), the prevalence of heart disease is lower among Chinese persons than among European persons. These observations led Woo and colleagues to compare endothelium-dependent vessel dilatation in smokers and nonsmokers from a village in southern China with that in smokers and nonsmokers from England and Australia. They found that although the percentages of vessel dilatation in the English and Australian nonsmokers and Chinese nonsmokers were similar (8.4% and 7.9%, respectively), the English and Australian smokers had less vessel dilatation than the Chinese smokers (3.9% and 7.3%, respectively). Woo and coworkers' study was well designed and well executed. Efforts were made to match English and Australian smokers and Chinese smokers for their degree of exposure to smoke, and the same ultrasonography technicians measured the extent of vessel dilatation by using the same type of equipment for all groups. This report therefore shows that, on average, Chinese smokers living in China do not have smoking-associated impairment of endothelium-dependent vessel dilatation.

Is the basis for this apparent protection genetic, environmental, or both? The authors argue that Chinese persons do not have a simple genetic advantage because the extent of vessel dilatation was similar for English and Australian nonsmokers and Chinese nonsmokers, but this argument is tenuous. The difference in vessel dilatation in smokers may be primarily genetic but becomes evident only on exposure to an environmental factor, such as cigarette smoking. Studies of immigrants have been useful for separating the environmental and genetic components of ethnic differences [4-6]. It would be informative, therefore, to measure vessel dilatation in Chinese smokers and nonsmokers living in Australia, the United Kingdom, or the United States. If the protection seen in Chinese persons living in China is also seen in westernized Chinese persons, the case for involvement of genetic elements would be strengthened. The role of genetic elements would not be proven, however, because immigrants may have brought protective factors, such as diet, with them.

Wall and associates [2] address the mechanism underlying the unpleasant sensations and facial flush experienced by many Asian persons after the consumption of alcohol. They describe the results of experiments in which Asian-American men underwent genotyping for the aldehyde dehydrogenase (ALDH2) gene and were then challenged with low-alcohol (placebo) and high-alcohol drinks. A variant allele of the ALDH2 gene, ALDH2*2, has been shown to result in reduced aldehyde dehydrogenase activity. This allele is very common among Asian persons (30% to 50% of Asian persons are deficient in ALDH activity) and rare in most other populations (for example, 0% of persons in Africa and Europe are deficient). The ALDH2*2 allele leads in a genetically dominant fashion to the accumulation of acetaldehyde in the blood after the consumption of alcohol [7].

Wall and coworkers found no significant differences in blood alcohol level between ALDH2*2 heterozygotes and persons who were homozygous for the normal allele at any point up to 150 minutes after the administration of alcohol. However, blood acetaldehyde concentrations differed significantly between the groups at several points. These results support and extend those of previous studies that have implicated the ALDH2*2 allele in the alcohol flush reaction and have suggested the importance of blood acetaldehyde concentration, not blood alcohol level, as the mediating agent [8, 9].

While recognizing the effects of ethnic variation, it is important to understand some of the pitfalls of ethnic classification. The concept of race and the study of ethnic variability were formalized by physical anthropologists at the beginning of this century. In the model of human evolution that prevailed at that time, ancestral populations were thought to have diverged early in human evolution (1 million to 2 million years ago) and to have evolved independently into modern human "races" on at least three continents. Inherent in this concept is the idea that "racial" populations are homogeneous with respect to many genetic traits and that persons in a particular "race" are biologically more similar to each other than to persons in other "races." In the past 20 years, significant support for an alternative model of human evolution, the out-of-Africa model, has been provided by studies of human genetics and archeological research. The out-of-Africa model posits that Homo sapiens originated in southern and eastern Africa 100 000 to 200 000 years ago and that all contemporary human populations are descended from this single African population.

Polymorphic genetic markers have been used both to support the out-of-Africa model and to directly assess the genetic affiliations of human populations. If the classic concept of race were appropriate, we would expect to find that many genetic markers are restricted to one population or one group of populations. In fact, such distinguishing markers are very rare: Of the thousands of markers that have been surveyed in multiple human populations, only one (the Duffy null allele, which confers resistance to Plasmodium vivax malaria) is found in 100% of African persons and 0% of other persons. When many genetic markers are considered together, one can apportion the total genetic diversity into that which results from differences among populations and that which results from differences among individual persons. Generally, about 10% to 20% of all human genetic diversity results from differences among populations; the balance reflects differences among individual persons. In other words, most of the genetic markers found in one population are found in others, and most of the genetic differences between two persons are not the result of coming from different populations but are the result of not being the same person (the obvious exceptions are identical twins and clones).

It is now clear that the classic concept of race established by the founders of physical anthropology is invalid. Human populations have had a very long period of common history; they only recently diverged into populations that are separate but that remain genetically very similar, and they have often rejoined through admixture. In addition, it is clear that some meaningful physiologic and morphologic differences among human ethnic groups exist (such as differences in drug metabolism [10] and muscle enzyme levels in response to exercise [11] and an association between keloids and hypertension [12, 13]) and that with an appropriate set of genetic markers, individual persons can be classified ethnically [14]. It is also important to remember that cultural differences between ethnically defined populations exist and must be carefully considered before conclusions are made about the role of genetic differences in physiologic traits or disease prevalence [15].

Focused, well-designed investigations, such as those by Woo and Wall and their colleagues [1, 2], are examples of the unique way in which observations of ethnic differences can be seminal in biomedical research. It was the observation of ethnic variation in response to alcohol consumption that initially led to studies on alcohol and aldehyde dehydrogenase [16, 17], now culminating in such studies as Wall and coworkers'. Other recent studies have focused on the importance of ALDH2*2 polymorphism in determining the risk for alcoholism [18], liver disease [19], and esophageal cancer [20].

Wall and colleagues [2] offer a conclusive study of a well-defined problem, whereas Woo and associates [1] present an intriguing initial observation that can and should develop into a larger area of research. It remains to be determined, however, whether protection from smoking-induced vascular dysfunction is caused by environmental or genetic influences (or both) and whether populations other than those in China are protected.