The Raymond Pearl memorial lecture, 1992: Ethnicity and disease—more than familiality

AMERICAN JOURNAL OF HUMAN BIOLOGY 5:373-385 (1993)

The Raymond Pearl Memorial Lecture, 1992: Ethnicity and DiseaseMore Than Familiality

WILLIAM J. SCRULL Graduate School o f Biomedical Sciences, University of Texas Health Science Center, Houston, Texas 77030

ABSTRACT It has long been recognized that the prevalence of many, possibly most diseases differs among different ethnic groups, and it is further known that cultural differences among people affect. the acceptability of measures to prevent or ameliorate a given disease process. Major public health challenges of our time are the delineation and understanding of how these differences in prevalence arise, and the fashioning of acceptable and effective intervention strategies. The web of causation is undoubtedly complex and in the unraveling there will be a need to examine new paradigms, new models of’ how genes and environments interact in the evolution of disease. These models must recognize the levels within the disease process where interactions can occur. This will demand a holistic rather than the reductionist approach that has obtained in the past. However, there are promising developments at the molecular and cellular levels, and the methods of data analysis grow progressively more sophisticated. This presenta- tion briefly describes the methods of and problems confronted by genetic epidemiology in the context of studies of ethnic differences in disease. 0 1993 Wiley-Liss, Inc

Through much of the first half of the present century, public health officials and epidemiologists stood in awe a t the suc- cesses of bacteriology. I t is understandable, therefore, that John Snow’s studies of the London cholera epidemics of 1853 and 1854 would be seen as the classic epidemiologic paradigm. Strangely, however, Snow’s well- reasoned book, “On the Mode of Communi- cation of Cholera,” had little or no influence on his contemporaries, and in fact, his belief that some small animalcule was responsible for the contagion was seen as misbegotten and inconsistent with the miasma theory in vogue (Krieger, 1992; Vandenbroucke et al., 1991). At the time, there was no disease with a known bacteriologic cause, and almost 30 years would elapse before Robert Koch discovered a commaform bacillus in Egypt in 1883, and held it to be the cause of cholera. As the years passed, it was recognized that not all individuals exposed to infection become infected and that not all infected individuals became ill, and the unicausal mode of thinking implicit in the Snow paradigm was slowly displaced by multicausal models of disease that attempt

to incorporate differences in host, agent, and environment into notions of etiology. Per- haps no place has this multidimensional view of causation been more obvious than in the epidemiology of chronic disease where it has led t o what Petr Skrabanek (1992) has termed the “association game.” He contends that epidemiologists now search for associations between the “diseases of civilization” and “risk factors” without regard to biologi- cal plausibility or any underlying hypothesis. As he puts it, “any combination of ‘exposure’ and disease. . . is fair game for calculating relative risks, odd ratios, or proportional hazards.”He states that this is not a new game, citing the current interest in the role of cabbage consumption in the occurrence of cancer and noting that Cat0 the Elder had commented on this two millennia ago. Cat0 suggested that the application of macerated cabbage can cure an ulcer of the breast or a cancer. Skrabanek (1991) further argues that risk factors are largely irrele-

Received September 25,1992; accepted February 6,1993.

0 1993 Wiley-Liss, Inc

374 W.J. SCHULL

vant to the search for causal mechanisms. They are risk markers, but they are neither sufficient nor necessary to explain the risk. He notes that at the last official count, in 1981, no fewer than 246 risk factors had been identified for coronary artery disease (Hopkins and Williams, 1981). Patently not all of these can be of moment, and this had led him to opine, “It is the intimation by epidemiologists that they (risk factors) hold the key to the causes of diseases and their prevention which makes them overstep their brief and join the moralists in their preaching how to avoid death by being good, clean-living citizens.” Are we in danger of raising ethnicity to a similar dubious posi- tion in the etiology of disease? It is this issue I propose to pursue through examining, in a general way, the inferences that can be drawn from ethnic studies.

We begin with several definitions, specifically those of disease, risk factors, ethnicity, and finally, genetic epidemiology since it is the tools ofthis discipline we use in studies of the relationship of ethnicity to disease. However, these tools have limitations which must be borne in mind when inferences are drawn.

The World Health Organization has defined health as a state of physical, psycho- loLGcal, and social well-being, and by infer- ence, disease is the absence of this state. Admirable as this sentiment may be, it is a definition that has not, and perhaps cannot, be made operational. Generally disease is defined in a less encompassing manner, as simply a “process that creates a state of physiological and psychological dysfunction confined to the individual” (Susser, 1973). This definition has the merit that it recog- nizes disease as a process, not merely a state of being, and implies a continuum of change from normality to ill-health.

Risk factors are those personal or situa- tional characteristics imputed to be causally related to disease. These include age, sex, ethnicity, weight, height, diet, habits, customs, and vices, on the one hand, and geog- raphy, occupation, environment, air, water, sunlight, electromagnetic fields, and the like, on the other.

As to ethnicity, Webster’s Dictionary tells us that it means “of or relating to races or large groups of people classified according to common traits or customs.” This definition is not much more helpful biologically than the World Health Organization’s definition

of disease, and too frequently, in practice, the term has varied with the requirements and orientation of the individual investiga- tor. Often ethnicity, as employed in the United States or the United Kingdom, has been a convenient rubric used in the decen- nial censuses, and confounds numerous sources of variation. Viewed from the genetic perspective, to be etiologically informative statements regarding ethnicity should capture in some way the genetic difference between groups of individuals, bear- ing in mind that the within group genetic variability will inevitably be greater than that between groups.

Finally, a few words about genetic epidemiology-it has been defined as the “science that deals with the etiology, distribution and control of disease in groups of relatives or with the genetic causes of disease in populations” (Morton, 1977). But it has also been described as the study of the interaction of environmental and genetic determi- nants in common diseases (Sing and Moll, 19821. Whatever the definition one favors, genetic epidemiology dif‘fers from conven- tional epidemiology in its perspective and its tools (Schull and Weiss, 1980). Most epidemiologists use statistical evidence-standardized mortality ratios, odds ratios, and the like-to establish associations and ar- gue from these associations to causality. Their studies commonly focus on prospec- tive or retrospective cohorts of unrelated persons or case-control comparisons, again usually involving unrelated individuals. Ge- netic epidemiologists, on the other hand, use statistical evidence to establish the existence of a gene and then to infer its role in disease causality. Their focus is on families or groups of individuals, such as paired siblings, whose genetic relationship, one to another, is definable. Often, in the past, these studies were based on “traditional markers,” such as the human blood groups, serum proteins, or cellular enzymes, but increasingly, attention centers on “candidate” genes, i.e., those genes where some prior biochemical or physiologic rationale exists to believe the gene(s) may be involved in the disease process. What is sought is evidence that a sub- stantial fraction of the variance in a trait cosegregates within families (or other groups of biologically related individuals) with a known, presumably linked, marker locus. Such cosegregation does not establish the existence of a major gene unequivocally,

ETHNlClTY AND DISEASE 375

but offers presumptive evidence and can serve to focus research on those genes with larger effects.

Genetic epidemiology can be said to have begun with Archibald Garrod’s study of the etiology of alcaptonuria and its distribution among the English (Garrod, 1902). This was the first population oriented study of a simple, mendelian disease. Others may dispute this origin, fixing a later date, but all would agree that genetic epidemiology did not begin to flower until the last several decades. Avariety of reasons can be advanced for why this was so. Rapid progress came only when laboratory methods were available that could provide deeper insight into the etiology of disease, a critical corpus of information had accumulated, and contemporary methods of data management and analysis were possible. These advances also brought changing standards for evaluating evidence purporting to show an association of disease with risk factors such as ethnicity. These standards are still evolving, particularly insofar as common chronic diseases are concerned where new molecular markers provide a specificity and certainty of information that has not previously been obtained. These caveats notwithstanding, the best way to understand the methods of and problems confronted by genetic epidemiology is through describing the research design and findings of major studies that have looked for risk factors within a given ethnic group or groups.

THE INTERACTION OF NATURE ANDNURTURE

Forty-odd years ago, Haldane (1946) noted that the interaction of nature and nurture is one of the central problems of genetics, and asserted that “We can only determine the differences between two different genotypes by putting each of them into a number of different environments.” In practice, in the human case, this is difficult to do since individuals or their environments cannot be manipulated generally, either for eth- ical or pragmatic reasons. As an alternative, “natural experiments” are sought, instances where historical and sociocultural events have provided the variability in genotypes and environments that is sought.

Research design Two such experiments are common-they

involve migrant populations and the occur-

rence of different ethnic groups residing in the same environment ostensibly. And to this list should be added admixture studies since they can define the genetic similarity between comparison groups and provide evidence on possible selection biases.

These three types of studies are overlap- ping, but not identical. Each has its own limitations. Migrant studies, for example, can be compromised by the selection bias known as the “healthy migrant effect,” or by confounding extraneous variables-cigarette smoking or drug usage-which impinge on the variable of interest, or by differences in the availability of medical care, or system- atic differences in the measurements among observers. But limitations aside, rarely, if ever, do migrant studies or the comparison of different ethnic groups residing in the same area provide the wisdom needed to assess nature-nurture interactions rigorously since even in the simplest case of two genotypes, two environments, and two criteria of performance there are no less than 72 possible interactions. Expressed algebraically, the number of possible interactions is lmn!lk/m!n!k!, where m is the number of genotypes, n the number of different environments, and k is the number of performance criteria used. Note that adding a single additional genotype t o the simplest case increases the number of possible interactions from 72 to 21,600. Now, to return briefly to the situation with respect to coronary heart disease, since the number of interactions increases multiplicatively, if only 10% of the ostensible 246 risk factors are, indeed, associated with this disease, and if the risk factor has a relatively simple genetic basis, the number of possible interactions will be in the hundreds of thousands. Clearly the sample size necessary to evalu- ate all of these will be astronomical. Under these circumstances, it is unlikely that all of the interactions can ever be evaluated, and to assess even a few will require very carefully designed studies.

Complexity of interactions: the Detroit Study As an illustration of the complexity of the

problem, consider briefly the Detroit Study (see Journal of Chronic Diseases, Volume 30, Number 10, 1977; Harburg et al., 1977). This was an ambitious effort to assess the role of psychosocial stress and genetic factors in the occurrence of hypertension and to account for the well-recognized higher prev-

376 W.J. SCHULL

alence of hypertension among Afro-Ameri- cans. It involved comparisons of Afro-Amer- icans and Whites residing in four census areas representing the extremes in socioecologic stress among the 382 tracts in Detroit. Variation in socioecologic stress was reck- oned on the basis of data on socioeconomic deprivation, residential instability, family instability, crime, and population density collected in a federally sponsored, citywide transportation and land use survey. These data were examined using factor analysis. Two major factors distinguishing census tracts emerged-socioeconomic status and instability. Factor scores were then used to rank all of Detroit’s census tracts, and from this ordering were selected predominantly Afro-American and White tracts with factor scores in the upper range for instability and lower range for socioeconomic status. These tracts were designated “high stress” areas, and the converse was used to select “low stress” areas. Interestingly, in the pilot study in 1965 preceding the major effort, the Afro-American area in Detroit deemed most stressful by these criteria was the one where the riot in 1967 erupted. Obviously this does not prove the validity of the rank ordering, but it suggests that the factor analytic approach identifies ecologic differences of social moment.

Once the study areas were defined, a complete census of dwelling units was conducted in each selected tract to identify a series of potential index cases. These individuals had to meet certain criteria with respect to age and marital status, and the availability of a defined set of relatives, specifically a spouse, a full sibling, and a first cousin. Matched t o each index individual was a comparison person of the same age and sex residing in the same census tract who also had available the defined set of relatives. Once the index cases and their “controls” were enumerated and verified, a public health nurse interviewed every member of the set. This interview was aimed at obtaining a medical history, demographic data, and information on self-perceived stress. In the course of this interview, which took approximately an hour and one-half, five separate readings of diastolic and systolic blood pressure were obtained by the nurses using a standardized protocol. Altogether 461 family sets, or 2,305 individuals were studied, and the index cases were distributed almost

equally over the eight “stress area”-sex-ethnicity strata.

Analysis of the data occurred at two levels, that of the individual and that of the family set. The purpose of the family set was to provide a means to assess the genetic con- tribution to variation observed since relatives share genes in a predictable manner-an index case will share half their genes with a sibling, and one eighth with a first cousin, for example. This fraction of shared genes is called the coefficient of relationship, and it can be used as an indepen- dent variable in regression analyses or for deriving heritability estimates. Moreover, with characteristics that show a strong age dependence, e.g., blood pressure, use of a family set mitigates confounding age-related variability since the members of the set, being generational contemporaries, can be so selected as to be of approximately the same age. To afford some evidence of‘ the internal consistency of this previously un- tried approach, two seemingly genetically simple but continuously distributed traits- stature and skin color-where a wealth of data exist on heritability were included among the measurement variables. In both instances, the family set method yielded heritability estimates that accorded well with the published literature. However, the findings with regard to the variable of pri- mary interest, socioecologic stress, were more ambiguous and did not reveal a consistent effect on blood pressure.

Given the care with which this study was designed and the numerous internal checks incorporated into it, one can be pessimistic about the likelihood of disentangling the pieces of the nature-nurture puzzle. But this pessimism seems unwarranted since studies such as that in Detroit should be seen as merely a first step, and the puzzle itself may ultimately yield more rapidly to the better measurements, particularly those a t a molecular or cellular level, that are now possible.

Migrant studies: the Ni-Hon-San Study One of the most comprehensive migrant

studies has been that known as the Ni-Hon- San Study. I t began almost 30 years ago, and continues albeit somewhat changed in direction. Initially it embraced three groups of Japanese-those living in Japan (Ni, for “Nihon,” the Japanese word for Japan), those in Honolulu (Hon), and those in the


San Francisco area (San) (Belsky et al., 1971). Three different collaborating centers were involved-the Atomic Bomb Casualty Commission; the Honolulu Heart Study, a National Heart and Lung Institute contrac- tually supported field investigation; and the School of Public Health at the University of California at Berkeley. Work was begun in Hiroshima and Honolulu in 1965, and in San Francisco in 1969.

The study was prompted by evidence that numerous factors, some intrinsic to the individual and some not, contributed to the occurrence of cardiovascular and possibly cerebrovascular disease. This evidence included information from presumably genetically similar groups of individuals living in different environments with different life- styles. But this information, which offered an opportunity to examine the effects of different environments on disease occurrence relatively free of the added influence of genetic variability, could be extended. And comparison of Japanese residing in Japan with those living elsewhere presented an at- tractive prospect, since the limited data available suggested that coronary artery disease among Japanese in the United States was much higher than in Japan. Cerebrovascular disease, on the other hand, appeared to be less common among the mi- grants than in Japanese still living in their homeland. If this information was correct, and if one could assume that on average the genetic constitutions of these groups were the same, then something(s1 associated with their change in lifestyle and environment affected their health.

The examinations, which employed a common set of components in all three study areas, included a complete physical exami- nation, a series of diet, health, and socioeconomic histories, an electrocardiogram, de- tailed laboratory studies to assess blood lipid levels, and where possible, pathologic studies. The investigations in Hiroshima and Nagasaki focused on males born from 1895 through 1924, and thus were between the ages of 40 and 70 when the study began. There were 3,322 such individuals in the morbidity surveillance that was already un- derway, and 13,126 in a parallel mortality surveillance. Examinations on the former had begun in 1958, and mortality had been under surveillance since 1950. As a consequence, there already existed 7 years of ob-

servations that could contribute to estimates of the prevalence of these diseases among the Japanese in Japan, and 15 years of mortality experience to examine trends in the occurrence of deaths attributable to cardiovascular and cerebrovascular diseases over time.

In the years that have followed the initial examinations, an unusual body of data has accumulated, one that captured the period when the prevalence of cerebrovascular disease in Japan began to fall and greater con- cern arose about possible changes in the prevalence of coronary heart disease stem- ming from the increasing “Westernization” of the Japanese diet, particularly the rise in the consumption of fat. To avoid confounding differences in medical care, culture, and language when comparisons were made of the incidence of coronary heart disease in Japan, Hawaii, and California, cases were restricted to those individuals in whom the occurrence of a myocardial infarction could be documented electrocardiographically. These comparisons revealed the frequency of infarctions to be the lowest in Japan, where values are one half those seen in Ha- waii, and still higher by 50% in California than in Hawaii (Robertson et al., 1976,1979; Takeya et al., 1984). However, similar comparisons of the incidence of strokes resulting from intracranial bleeding or a blood clot indicate that the incidence in Japan is about three times higher than that in Hawaii. Why this should be so is not known; however, it has been suggested that this difference may be attributable to differences in Oriental and Western diets. The traditional Oriental diet has been low in the consumption of animal protein and saturated fat, whereas in Western diets consumption of these foodstuffs has been high. Experimental studies suggest that animal protein and saturated fat have an inhibitory effect on the occurrence of stroke, and during the years of this study both were more commonly consumed by Japanese living in Hawaii than those living Japan.

Cerebral infarction generally occurs either as a consequence of sclerotic changes in the small vessels of the brain or through the deposition of fatty materials in the walls of the system of arteries a t the base of the brain known as the circle of Willis. Inter- estingly, pathologic investigations in Hi- roshima, Nagasaki, and Honolulu growing

378 W.J. SCHULL

out of the Ni-Hon-San study suggest that small vessel sclerosis is substantially more common in Japan than in Hawaii, but atherosclerosis of the circle of Willis is more severe in Hawaii. This has led to the further conjecture that the foodstuffs alluded to above may suppress the onset and development of small vessel sclerosis. While the data are consistent with this notion, there is no direct evidence to support it and other explanations could be advanced.

Although the studies in San Francisco have ceased, observations continue to be made in Honolulu, Hiroshima, and Na- gasaki, and comparisons of the two sets of data still occur, but the thrust has shifted- greater emphasis now rests on the process of aging. Ironically no effort has yet been made to 1) define the genetic distance existing among the three groups of Japanese males that have been compared, and thus t o examine the assumption about the genetic compa- rability of the three samples, or 2) examine the correspondence in experience among the relatives within the three cohorts. As to the “average” genetic similarity among the three groups, extensive serologic data exist on the cohort in Hiroshima and Nagasaki, but not on the Honolulu or San Francisco samples and may no longer be obtainable because of the death of many of the original participants.

This early interest in atherosclerosis among the Japanese has taken on added value as data accumulate suggesting that mortality attributable to causes of death other than cancer, and in particular cardiovascular disease, might be elevated among the atomic-bomb survivors. Until recently, it has been assumed that the only life-shorten- ing occurring among the survivors was as- cribable to their significantly increased risk of cancer, but since this no longer appears to be true, an explanation must be sought for the apparent increase in heart disease with increasing dose. One now appears to be emerging. The evidence is as follows.

Coronary heart disease and strokes are the culmination of a process involving the medium and large arteries of the body that normally develops slowly over many years. Within these vessels a fatty infiltration of the smooth muscle cells of the arterial walls occurs, giving rise to discrete plaques or atheromas. It has been generally thought that these plaques result from the repair of

repeated injury to the arterial wall. How- ever, a less common view holds that atheromas are actually benign tumors derived from changes in a single cell. The evidence supporting this belief rests on the characteristics of the cells within the plaque. They all appear to have the same genetic properties, suggesting they are clonal in origin, whereas this is not true of normal arterial tissue existing where the cells are phenotyp- ically dissimilar. This finding has led to speculation on the role that heritable changes, arising through mutation in the genetic material in smooth muscle cells, could play in plaque formation. Heretofore there has been little direct evidence t o support the occurrence of presumptive but potentially meaningful mutations. However, experimental studies have now been published that suggest the changes in the arterial walls associated with atherosclerosis might have a cellular basis similar to that seen in cancer, including the occurrence of somatic mutation (Penn et al., 1986; Scott, 1987).

These studies have shown that DNA extracted from plaques in the coronary arteries of humans when transfected into the cells of mice can produce tumors. The tumors are histologically indistinguishable from those produced in genetically similar rodents by DNA from human bladder cancer. Unlike the aggressive behavior of most malignant tumors, however, those produced by plaque DNA grow more slowly and result in relatively fewer tumors in the recipient animals. DNA extracted from the normal arterial wall of a human does not produce these results. This prompts the belief that a mutation has occurred leading to the activa- tion of one or more proto-oncogenes. Many of these latter genes have been described, but it has not been established which one, if any of those presently known, may be involved in plaque formation although a number of candidates exist (Scott, 1987).

Migrant studies had been initiated by anthropologists even before the beginning of the Ni-Hon-San study: indeed, among the earliest, if not the earliest, was Boas’ studies comparing differences in the form of the head of immigrants from a variety of locali- ties in Europe with their children born in the United States. Most of these investigations, for example, Gabriel Lasker’s studies of the children of immigrant Chinese (1946), focused on growth and development, were


substantially less ambitious, and generally did not have clinical observations to support the anthropologic studies. There are excep- tions to this statement, of course, such as the studies of Ian Prior and his colleagues in the Tokelaus and among the Maori. But times have changed, and anthropologic studies of the association of the ethnicity with disease are now more sophisticated.

Associations of ethnicity and disease: diabetes

The study of diabetes exemplifies these changes (West, 1978). I select diabetes: specifically non-insulin-dependent diabetes (NIDDM), for two reasons. First, since the promulgation of James Neel’s “thrifty genotype)’ hypothesis (1962, 19821, diabetes has probably attracted the interest of more anthropologists than any other common disease, and second, these changes can be illustrated through our experiences with this disease among Mexican Americans residing in Starr County, Texas.

This study, which began over a decade ago as a cross-sectional one, has become longitudinal (Hanis et al., 1983). It was prompted in large measure by the clinical impressions of physicians practicing in Starr County as well as in the other 10 counties along the Texas-Mexico border. At the time, it was already known that considerable ethnic variability existed in the prevalence of diabetes mellitus, and therefore their conjectures were plausible, if undocumented. To test their assertions we turned to statewide data on cause-specific proportional mortality. The results, illustrated in Table 1, were suf- ficiently dramatic t o warrant more careful study. Specifically, the findings posed three broad questions. What are the sources of the high prevalence of diabetes? Are there underlying commonalities for this disease and the others, e.g., gallbladder disease, known to be increased in this segment of the population? Arc the manifestations of the disease the same as in other populations? To ad- dress these questions, over the succeeding 10 years, 4,000 Starr County residents, about 20% of the adult population of the county, have been physically examined. The findings can be briefly summarized as follows: Age-specific prevalences of diabetes are three to five times higher than in the general population of the United States. Over 30% of the diabetics present with significant

TABLE I . Diuhctcs mortality in Texus 1970-1981

Diabetes dcaths/1,000 % Spanish County deaths origin

Highest rates Starr LaSalle Brooks Webb Maverick Haskell Kleberg Hidalgo Dimmit Mitchell

Lowest rates Dallam Somervell Archer Deaf Smith Red River Brown Kendall Clay Brewster Blanco

52.0 51.6 45.6 43.6 35.3 34.1 32.1 31.5 31.1 30.8

2.5 3.8 6.7 5.8 7.5 7.8 7.9 8.3 8.3 8.9

97.9 78.4 79.9 85.6 90.3 13.0 43.9 79.1 81.7 24.7

17.5 ~ ~ ‘ 1 4 . 3 4 . 9 36.3 <2.8

5.4 20.3 15.0 47.8 11.2

retinopathy, and each year in another 10% retinopathy appears or progresses. Annual mortality is several times higher among the diabetics than among individuals of compa- rable age and gender. The salient risk factors to emerge are 1) Mexican American or Amerindian ancestry, 2) obesity, including body fat distribution and the velocity of weight gain, 3) age, and 4) family history (see also Stern, 1985; Stern et al., 1981). Finally, it is important to bear in mind that the Mexican American population is a young one, and as a result the burden of ill-health attributable to diabetes can only increase in the future.

Some of the findings enumerated above are, of course, not unexpected. We have, for example, long known that diabetes aggre- gates in families. And the recognition of two main forms of this disease-insulin-dependent diabetes mellitus (IDDM) and NIDDM, respectively,-has not changed the percep- tion of aggregation. It has led, however, to differences in suggested genetic etiologies. Paradoxically, the rarer IDDM shows much weaker familial aggregation than does NIDDM, but it is for IDDM that more basic genetic mechanisms have been proposed (Rotter, 1981; Louis and Thomson, 1986). In large measure, the driving force behind the genetics of IDDM has been the demonstra- tion of its clear association with the HLA

380 W.J. SCHULL

haplotypes DR3 and DR4 (Thomson, 1988). It has been proposed that a t least one IDDM susceptibility locus is in the HLA-D region (Foster, 1989). Interestingly, among Afro- Americans there is a strong association between IDDM and the HLA-B8 and B15 haplotypes (Rossini et al., 1988). In spite of the implied genetic factors, concordance of IDDM in identical twins is less than 50% and is approximately equal to the risk in full siblings sharing both DR3 and DR4. When siblings share neither DR3 nor DR4, the risk is less than 1% (Foster, 1989). No genetic model yet proposed explains the various empiric recurrence risks.

In contrast, no strong associations with particular genetic markers have been identified for NIDDM, but familial aggregation is much stronger than for IDDM and the health burden imposed on many populations in transition is much greater. Concordance of NIDDM for identical twins is more than 90% and empiric risks in first degree relatives are similarly higher than is the case for IDDM (Foster, 1989). This stronger familial aggregation has not yielded to explanation by straightforward genetic models. This is not to say that there is no additional information implicating genetic factors beyond simple familial aggregation which can result from both shared genes and shared environments. Indeed, epidemiologic and genetic studies of ethnically distinct populations have provided some of the most compelling evidence for the role of genes in the distribution of NIDDM. Native American Indian groups have been shown to have extremely high prevalences of diabetes. This has been most fully documented among the Pima In- dians of Arizona (Knowler et al., 1978). Ge- netically admixed groups having Native American Ancestry, such as Mexican Ameri- cans, have rates of diabetes that are proportional to the degree of Amerindian ancestry (Gardner et al., 1984; Hanis et al., 1986). That the pattern is consistent among various Amerindian and admixed groups across widely differing environmental strata leads one to presume a genetic mechanism (Weiss et al., 1984), although it must be noted that it is difficult to preclude all other causal mechanisms such as responses to the childhood environment, including age-dependent consequences of infection and adaptation to diet early in life (Barker, 1989). Here studies of diabetes in unacculturated or moderately acculturated Indian groups, such as Szath-

mary’s among the Dogrib (1990) or Weiss’ among the Lacandon (19901, are especially informative.

Focus on genetic factors: molecular biology The implied genetic role in NIDDM and

description of the numerous metabolic path- ways that can be altered as a result of diabetes have led to the search for specific genetic loci whose alleles result in differential risk. Obvious candidates are the genes involved in carbohydrates metabolism including the insulin gene, insulin-like growth factors, insulin receptor, and the numerous glucose transporters. Rare mutations in the insulin gene produce abnormal insulins and can lead to diabetes (Bell et al., 19871, but such rare mutations have little public health impact, and are incapable of explaining the differences in prevalence that are seen. Initial reports of an association of the 5’ hypervari- able region of the insulin gene led to attrac- tive scenarios of common genetic variability leading to diabetes susceptibility, but the results have not held (Foster, 1989). Recent work among diabetic Chinese Americans examining variability at the above genes and also several lipid-related genes identified significant, albeit small, associations. Vari- ability at the insulin receptor, apolipoprotein B, and the apolipoprotein A-UC-IIUA-IV structural genes was implicated (Bell et al., 1987). Of particular interest in this work was the attempt to take account of association in different obesity classes. Generaliza- tion of these results awaits confirmation in other population or ethnic groups.

If they cannot be generalized this will not necessarily imply that the results among Chinese American diabetics are spurious. Epidemiologic studies have clearly established that the impact of a given disease is not consistent across populations. Likewise, genetic studies have repeatedly demon- strated heterogeneity of gene frequencies among populations so that it is possible to find heterogeneity of associations. This underscores the need for caution in inferring etiology from associations and requires that such putative associations account for population heterogeneity and alternative explanations. An illustration of the problem is the distribution of Gm haplotypes among the Pima and Papago Indians. Knowler et al. (1988) clearly show that an apparent strong association with NIDDM is explained by admixture. That is, the haplotype is a marker

ETHNlClTY AND DISEASE 38 1

of Amerindianness which happens to be highly correlated with diabetes risk. Hence, ignoring population genetic structure would have led to erroneous inferences.

Ethnic studies should. wherever possible, include genetic linkage analysis since this can provide alternative insights into the role of specific genetic loci and disease. Investi- gations of Caucasian (Elbein et al., 1988) and Afro-American (Cox et al., 1989) pedigrees, using markers at the insulin gene, have concluded that the insulin gene region does not account for NIDDM susceptibility and, in fact, can be ruled out as a candidate locus (Cox et al., 1989). In both studies, a variety of genetic model-dependent and model-free approaches were used and yielded similar results. Similar conclusions were drawn for the insulin receptor locus (Cox et al., 1989), but it was this locus that was implicated in the association studies above (Bell et al., 1987). Several factors may account for these apparently different results. First, linkage is not synonymous with association nor does association imply linkage (Vogel and Motulsky, 1986). Second, the association study found that there were haplotypes that resulted in reduced diabetes risk, hence the focus was different. Lastly, these are quite different populations.

Recently, family studies of maturity onset diabetes of the young (MODY) have suggested linkage between this gene (or genes) with the adenosine deaminase locus (ADA) (in a Michigan pedigree; Bell et al., 1991; Cox et al., 1992) and glucokinase (GK) (in French families; Froguel et al., 1992). Since ADA and GK are located on different chro- mosomes (ADA on 20q, and GK on 7p), either two different genes have been identified or one or both findings are spurious. It warrants noting, however, that the French families did not exhibit linkage to ADA, and that the linkage reported in the Michigan study involved the use of 79 DNA markers of which ADA was the only one to cosegregate. A priori, since GK is a key enzyme in main- taining blood glucose homeostasis, it would appear to be a better candidate gene. Confir- mation of one or both linkages is obviously needed, and should involve not only these specific genetic loci but others known to be closely linked. Some steps have been taken in this direction. Further studies in France have shown that in several families exhibit- ing a strong linkage of MODY to the GK locus there is a nonsense mutation at the

latter site (Vionnet et al., 1992). However, while this mutation may be relevant in some instances, it seems unlikely that it is a major contributor to the occurrence of NIDDM since it has been found in only 8-10% of affected individuals (Tanizawa et al., 1992).

The themes above will undoubtedly be ex- panded in the years ahead and the results will affect the direction of future research. Our understanding of metabolic and molecular events can only increase, but this increase is apt to be accompanied by concomi- tant increases in complexity. With increased description of the events, there should be an enlarged understanding of their regulation. Whereas heretofore the focus of research has necessarily been on structural loci, the greatest potential will lie in examining gene regulation. Heterogeneity within and between populations will continue to be trou- blesome and underscores the need for 1) carefully defining the population of infer- ence and 2) using more standardized proto- cols across population groups.

Need for research on diabetic complications and intervention

Two other areas of research that will become increasingly important relate to complications and interventions. Discussion here has been limited to simple presence o r absence of diabetes, but it is the understanding of differences in the development of complications between ethnic groups and appro- priate intervention strategies that will have the greatest health impact. In large measure, both require longitudinal studies such as those among the Pima Indians or in Framingham. Longitudinal studies can identify premonitors of disease such as obesity that are present long before the development of clinically overt disease. This long time element will only increase the diffi- culty with which effective intervention strategies can be designed, invoked, and as- sessed. In this regard, a particular strength of genetics is the focus on pedigrees. Gener- ally intervention strategies are discussed in terms of populations vs. high risk individuals. For diseases such as diabetes with strong familial aggregation and a long pre- disease state, family based intervention strategies may offer the greatest potential (Schull and Hanis, 1990). Educational and other noninvasive approaches may prove extremely powerful in family based settings where the unit of intervention is a high risk

382 W.J. SCHULL

pedigree, but the efficacy of these approaches will hinge on the cultural milieu, and here anthropology can be especially helpful since anthropologists are more at- tuned to assessing cultural differences than the bulk of epidemiologists. A last comment regarding the interface between the molecular approaches and intervention relates to genotype by environment interaction. It must be remembered that while a great number of potential markers are being examined and most will have small if any effects, it is possible that some alleles may be particularly sensitive to environmental ma- nipulation (including medication) and yield results that surpass expectation based on association studies.

THE FUTURE Genes are not static in their action, and

the need to know how this action changes with time looms progressively larger in the understanding of disease. We have been too preoccupied with the near events to discern adequately the etiologic roots of disease. As the evidence builds that many chronic disorders have their origins in childhood, greater emphasis will be placed upon the nature of gene-environment interactions in the ear- lier years of life. This will increase the need to examine new paradigms, new models of how genes and environments interact in the evolution of disease. These models must recognize the complexity of the disease process and the levels within this process where interactions can occur. They will demand a holistic approach that the reductionist phi- losophy prompted by the recent advances in molecular biology has eschewed. This will oblige us to consider other strategies of intervention beyond the traditional ones which have focused either on control at the population level, where efficacy has been challenged (McCormick and Skrabanek, 19881, o r among putative high risk individuals. We will see the family more frequently become the unit of intervention, particularly in diseases such as NIDDM. As Childs (1989) has cogently argued, disease is as much an expression of individuality as any other human characteristic, and while it may be impractical to tailor public health measures to the individual, this ideal would be more nearly approximated if directed to- ward the family.

Ethnic differences in susceptibility to viruses Studies of host susceptibility to disease,

particularly those of viral or putative viral origin, will increase in number and sophisti- cation. They will seek to determine the role of genes in the susceptibility of the host to disease, the course of disease once infection occurs, and the response to therapy (Flewett, 1986). Presently, surprisingly little is known about ethnic differences in viral disease, and much of what is known is based on the seroepidemiology of women in ante- natal clinics. For example, vertical transmission from the mother to her baby is the most common route of infection with the hepatitis B virus (Okada, 1976). However, there are major differences among ethnic groups in the rates of a e-antigen expression. White women rarely express this anti- gcn and hence their infants are not at risk, but most Chinese women are e-antigen posi- tive and their infants become carriers irre- spective of where the mother resides. The health implications of this fact are enor- mous. Viewed globally, hepatocellular carcinoma is one of the worlds most common can- cers, and it has been estimated that in 75- 90% of such instances the hepatitis B virus is the etiologic agent. Hepatitis B virus DNA is almost universally incorporated into the genome of hepatocytes of individuals with chronic infections as manifested by a posi- tive response to HBsAg; yet other individuals apparently eliminate the virus and de- vclop protective antibodies (anti-HBs). Why this should occur is presently unknown, but there is ample basis for speculating that this variability is response to the virus is genetic.

Evolutionarily the hepatitis B virus is probably related to the retroviruses, and the existence and influence of viral restriction genes have been extensively documented in animal models. Some block retroviral incor- poration into the host genome, still others apparently block viral replication. The role that such genes may play in human hepatocellular carcinoma, or in human oncogenesis more generally, is unclear but the delineation of their effects would certainly seem a fruitful area of study.

Strikingly similar statements can be made with respect to the human T-lympho- tropic virus type I (HTLV-I), which is commonly transmitted from a mother to her child through breast milk. HTLV-I is the cause of adult T-cell leukemia/lymphoma


(ATLL), and thus far the latter disease has only been seen in HTLV-I carriers. It develops at a frequency of about 1 in 1,500 carriers each year. The virus is endemic in south- western Japan. HTLV-I seropositivity in healthy adults in JSagoshima prefecture, for example, is reported to be 11.9%. As a result, there is also a high incidence of ATLL (approximately 100 cases each year). ATLL is resistant to any currently available treat- ment and has a very poor prognosis, almost 100% of cases are fatal within 2 years. At present, the most effective measure to control HTLV-I endemicity is the prevention of infection.

Needed research directions Further research can also be anticipated

on genetically determined variation in response to environmental carcinogens, muta- gens, and teratogens, and to pharmaceuti- cals. Hopefully we will also see the means to study genetic variation in the regulation of metabolic processes. Now we are largely limited to examining variability a t genetic loci coding the structural form of proteins, presuming that variation in these genes al- ters risks. Obviously regulatory genes would be a more fruitful area of inquiry, and the sequencing of the human genome may provide the necessary evidence into the location and organization of such genes. Most studies of the association of disease with ethnicity have been cross-sectional, but there is a real need for longitudinal investigations since the process we seek to reveal is a dynamic, a continuing one, and adaptation is played out over time.

These are, of course, speculations, but one thing seems certain. As the character of national populations change through migra- tion, differential birth rates, and the like, ethnic factors in health and disease will become more important and not less (as testi- mony see, e.g., Cruikshank and Beevers, 1989; Polednak, 1989). As we have previously said, there will be a greater need for health providers to examine these factors systematically and thoroughly if the bene- fits of modern medicine are to be equitably and effectively disseminated. But this exam- ination will be puerile if i t becomes a statistical exercise devoid of human commitment. Our health problems are not merely events to be counted, they are individual tragedies. Their resolution does not depend upon a

mathematically more sophisticated test of linkage, a more elegant laboratory proce- dure, or even a larger database. It depends upon the formulation of plausible, testable hypothesis. Plausibility, however, implies some understanding of the biologic processes involved and this, in turn, obliges us to think as human biologists first, and disci- plinary advocates second. We must ask our- selves continuously whether the results of a study are “reasonable,” do they accord with prevailing scientific wisdom. If they do not, there should be a rational biologic argument as to why they do not. Arguably the greatest disservice as scientists we have imposed upon the societies of which we are members is the so-called “hypothesis generating” study. These studies are too commonly an abrogation of reason and the scientific method.

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Documents

The Raymond Pearl memorial lecture, 1992: Ethnicity and disease—more than familiality