Genetics and public health in the 1990s.

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GENETICS AND PUBLIC HEALTH IN Annu. Rev. Public Health 1990.11:105-125. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/20/15. For personal use only.

THE 1990s William J. Schull and Craig L. Ranis The Genetics Centers, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77025

INTRODUCTION Public Health has traditionally been concerned with the identification, preven tion, and control of diseases in populations_ The instrument of investigation is and has been epidemiology, traditionally defined as the science of epidemics and epidemic diseases, that is, those which attack many people in a communi ty or population_ Control proceeds through the screening of populations for affected individuals and the formulation of public policies designed to prevent the occurrence of disease or to mitigate its severity. These policies may provide for treatment and education of affected individuals, removal of sources of disease or disability, and protection of individuals and populations. Genetics has heretofore played a small role in these activities. Two atti tudes seem largely responsible for this. First, it has been commonly assumed that simply inherited diseases are relatively infrequent and intractable insofar as conventional methods of public health control are concerned. It has been virtually axiomatic that a given genotype will result in the same phenotype in all environments. This supposition, however, disregards the wealth of evi dence that points to the dependence of gene expression on the environment in which that expression occurs, i.e. that a genotype that may be advantageous or at least neutral in one environment may be disadvantageous in another. Second, public health traditionally focused primarily on epidemic disease, where it is supposed that the disease is not continuously present in a particular group of individuals, but rather is brought from the outside through a transportable agent or agents, often bacterial or viraL Charles Creighton's monumental

History of Epidemics in Britain (20, 21),

for example, deals

solely with bubonic plague, cholera, diphtheria, influenza, smallpox, typhoid

105 0163 7525/90/0510-0105$02_ 00 -

Annu. Rev. Public Health 1990.11:105-125. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/20/15. For personal use only.

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fever, typhus, and the like. Words such as genetic or inherited do not even occur in this account of 12 centuries of epidemics. Among industrial nations, epidemiology has now expanded to a consideration of the common chronic diseases; Still, words like genetic and inherited are infrequently encountered. Increasingly, though, the technologic explosion in genetics and molecular biology is being applied to those chronic diseases of public health importance. What, however, can this new genetics offer public health? It is the purpose of this presentation to trace briefly the past role of genetics in public health, to identify some recent trends, and to speculate on the prospects for the future. Focus is on those diseases having the greatest impact on populations rather than simply inherited diseases that are individually rare. Collectively, these individually rare diseases may affect a significant propor tion of the population, but their impact is dwarfed by that of the chronic diseases. For example, estimates from population-based surveys in British Columbia indicate that prior to age 25, 5.3% of all live-born individuals will be affected with a disease having primarily a genetic component (7). By contrast, continuing studies among Mexican-Americans in Starr County, Texas, have established that 33% of the population 15 to 44 years of age are affected by one or more chronic disease problems, including non-insulin dependent diabetes mellitus, gallbladder disease, obesity, and hypertension. Among those 45 to 74 years of age, 71% are affected by one or more of these chronic disease conditions (49). HISTORICAL PERSPECTIVE References to familial disease are as old as the medical literature itself, but the emergence of inherited variation as a factor of importance in public health began arguably with Karl Landsteiner's discovery of the ABO antigens and the subsequent demonstration that these antigens were inherited properties of the red blood cell (11, 72). This discovery and the evidence of the Hirschfelds (53) that human populations differed in the frequency of the genes responsible for these antigens provided the impetus to search for other antigenic differ ences among individuals and ultimately culminated in the myriad distinct antigenic systems now known (see e.g. 98, 104). Further clinical significance was given to this search by the recognition that erythroblastosis fetalis, or more broadly hemolytic disease of the newborn, arose as a consequence of an antigenic incompatibility between the mother and her fetus (76), and that still other antigenic systems, notably the major histocompatibility complex (MHC), were instrumental in determining the success or failure of the transplantation of tissue from one individual to another. These findings, coupled with a steadily growing list of inherited differences in the proteins found in human serum and in the enzymes of the red and white


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blood cell (see e. g. 39), prompted a wider series of disease-gene marker association studies. The notion or hypothesis that undergirds such studies is simple. If there is no genetic basis to the disease in question, the disease should be equally represented among all marker alleles. If this is not true, there is presumptive evidence that the marker gene, or more probably a closely linked one, is involved in the causation of the disease. This approach has its limitations. For example, when the number of alleles at the marker locus is exceptionally large, as in the case of the MHC or in the use of certain restriction fragment length polymorphisms, chance or spurious associations are to be expected, and the separation of these from "real" ones is a significant undertaking. Often these associations arise through unrecognized ethnic vari ation in the disease frequency, or other sources of inadvertent stratification. In many studies, the locus is actually composed of several very closely linked loci that tend to be inherited as a unit (i.e. haplotype). If the number of haplotypes is large, some may not be represented at all even in very large samples, and thus certain gene associations cannot be tested (113). It can be argued, of course, that extremely rare haplotypes will have little public health impact, and that therefore their inclusion is not important. Haplotypes in frequent in one population, however, can be common in another. In addition, if a haplotype is rare, but all individuals with that haplotype have a particular disease (though only a small proportion of all diseased individuals may have the haplotype), this may lead to fundamental insights about overall disease etiology. Concurrent with the recognition of the extent of genetic variation, molecu lar biology and human cytogenetics came of age. Pauling and his associates (94) were able to show that sickle cell anemia was a "molecular" disease, the structure of DNA was elucidated (125), the human karyotype was un ambiguously defined (120), and the role of chromosomal abnormalities in the etiology of disease was documented (34, 56, 74). These advances in conjunc tion with amniocentesis, prenatal diagnosis, and selective abortion offered methods of disease control not previously possible. This new window of opportunity addressed a class of diseases each of which was relatively in frequent, although in aggregate they were common. Compared to common chronic diseases, these disorders had and continue to have a smaller impact on public health in the United States generally. Nonetheless, they have enormous consequences for specific individuals and families, or, for that matter, groups of individuals. Furthermore, geographic and ethnic variability in the frequencies of single gene disorders impose significant burdens on some groups not imposed on others, such as thalassemia among the Mediterranean peoples or sickle cell disease among blacks. These developments also served to establish the ubiquity of heterogeneity in diseases previously presumed to be homogeneous and began the detailing of the extensiveness of genetic


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variability within and between human groups. Even malaria, possibly the most prevalent human disease viewed globally, appears to be an exquisitely choreographed interaction of the genomes of the plasmodium, the mosquito, and man. Specific genes, such as those responsible for the Duffy red blood celJ antigen or sickle hemoglobin, can affect the probability of infection as well as the course of the disease. The search for markers of disease continues, but now to the array of markers used has been ad�ed restriction fragment length polymorphisms (RFLPs) and other DNA sequence variants detected through such methods as the polymerase chain reaction (see 38 and 129 for reviews). With these technological developments has come an expansion of studies of disease and marker association to the consideration of the effects of marker loci on quantitative phenotypes such as cholesterol (22). An additional point requiring mention is the rapidity with which public health measures can be instituted given development of appropriate biological information. Phenylketonuria (PKU) is a classic inborn error of metabolism characterized by a deficiency of the hepatic enzyme, phenylalanine hydroxy lase. In the early 1950s, dietary therapy was recognized as an avenue to alleviate the concomitant retardation that occurred with the mutation ( 12), but no effective screening modality was available. Screening became practicable in 1962, and within just a few years, nearly every state instituted legislation requiring screening of all newborns (see 17). Several issues are illustrated by this case. First, treatment exploited the metabolic events that had been described. Second, the treatment represented altering the consequences of a clear genetic trait through environmental manipulation. Third, rapid im plementation of a widespread public health response only occurred when effective screening and treatment became available. GENES AND COMMON DISEASES Over 20 years ago, at the University of Michigan, one of the first attempts was made to establish a conversation between geneticists and epidemiologists in the study of common chronic disease (90). No specific effort was made to define the conjunction of the two disciplines, but the proceedings speak to the differences in perspectives and expectations and the difficulties in establishing a common framework for discussion. There was nevertheless a recognition that despite these difficulties, genetic variation impinges on every disease, and that informed intervention in the diseases currently of paramount public health importance, namely, cardiovascular and cerebrovascular disease, can cer, diabetes, hypertension, obesity, and gallbladder disease, would require deeper insight into the nature of genotype by environmental interactions than then known. How are these insights to be obtained? A seemingly necessary requirement



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is the characterization of specific genotypes and specific environments. Fortu nately, insofar as many of these disease are concerned, a variety of well studied biochemical processes exists with which the unraveling of such interactions could begin. These include, for example, the metabolism of cholesterol, of carbohydrates, of bile acids, of fat, and the sodium, lithium and potassium transport pathways. Similarly, the existence of a series of cancer-predisposing genes, such as those associated with retinoblastoma and ataxia telangiectasia, and newer techniques have begun to reveal the nature of oncogenesis at least with regard to certain malignant tumors. Many insights will continue to come from the application of Garrod's notion of "treasuring our exceptions," that is, the careful scrutiny of single gene diseases, but still others will come from understanding the metabolic and genetic events that are responsible for normal variation. From the perspective of public health, it will be necessary to determine to what extent disease endpoints or compromised health represent heterogeneous discrete phe nomena and to what extent they represent extremes of a more continuous distribution. It would seem that greater insight will come from incorporating biochemical and molecular mechanisms into well-defined genetic, epidemiologic, and family studies. As support for this statement, it warrants noting that while Pauling and his colleagues were demonstrating the electrophoretic differences in the hemoglobin present in normal, trait, and sickle cell anemic individuals, Neel was using conventional family studies to reach the same genetic conclusions (88). In retrospect, each approach en hanced the other. Similarly, much of the focus on cholesterol and its role in cardiovascular disease has resulted from popUlation investigations, not so much from molecular biology, but the latter is elucidating the mechanisms that may be amenable to manipUlation. Now we increasingly see epidemio logical studies incorporating the newer molecular data, while molecular biologists are asking questions relating to impact of basic variability in populations. Meanwhile, genetics continues to be of relevance at all levels (see e.g. 89). Before speculating on the 1990s, we briefly review the interface of genetics and public health in the context of cancer, diabetes, and obesity. Our intention is to describe recent trends, not to defend the importance or long-term pertinence of any of these specific developments. Cardiovascular disease illustrates the same issues, but is not included because many recent reviews adequately give the necessary background (see e.g. 33 and 55). Although we have separated these topics and provide a quite narrow view of each, it would be misleading to suggest that they can in fact be separated. The common chronic diseases are not isolated events: They share overlapping metabolic pathways, coaggregate in families and popUlations, and are associated in a variety of fashions; treatment of one may compromise an individual's status

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with regard to another. Two general themes are illustrated; namely, heterogeneity within and among populations, and genotype by environment interactions.


Cancer The literature on the role of segregating genes in the occurrence of most common cancers is formidable, often contradictory, and places as big a burden on the reader's perseverance as perspicacity. Nonetheless, a familial aggregation of many of these cancers has been repeatedly reported, including breast cancer (see e.g. 29 or 91), cancer of the ovary (83), colorectal cancer (66), and cancer of the lung. Indeed, Schwartz, Boehnke & Moll (108) have estimated that among cancers overall, some 27% of the variability in cancer occurrence within families is due to familial factors. This is not synonymous with saying that 27% of the variability is genetic in origin, for most studies of aggregation do not, often cannot, distinguish between genetic and shared environmental factors. This fact notwithstanding, site-specific aggregation generally obtains irrespective of the magnitude of the age-adjusted mortality rate. For example, although mortality from ovarian cancer has been gradually rising in Japan, it remains among the lowest in the developed countries. Yet, a history of a breast, uterine, or ovarian cancer in a mother or sister is one of the most striking risk factors associated with ovarian cancer in a Japanese woman (83). Similar findings have been reported in the United States where ovarian malignancies are much more common (107). Substantial strides have been made in elucidating the genetic bases of some of the rare malignancies, such as retinoblastoma (66), but progress in the common cancers has been much slower, and much of the evidence for the familial occurrence that exists rests on traditional methods of genetic analysis. These methods are particularly sensitive to heterogeneity, and not only is there genetic heterogeneity in cancer, but nearly every cancer has been reported in a hereditary form as well as a nonhereditary form (66). It is hoped that recent developments here, too, will bring greater knowledge of the function of genes in the initiation, promotion, conversion, and progression of a malignant tumor. We cite three such developments. First, distributed through the human genome are a number of genes, commonly designated protooncogenes, whose roles in cancer causation are still poorly understood. In another form, as oncogenes, they can cause neoplastic growth and are presumably not solely adventitious. Many of these oncogenes have a normal role to play in cellular proliferation and differentia tion, and the specific function of a number of them is known. Their products are growth factors, growth factor receptors, transmembrane signaling pro teins, and the like. Some 50 or so of these oncogenes are already known (for



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reviews see 13 and 93), and the list continues to grow. Commonly, alterations or amplification of these oncogene sequences are observed in malignant tumors. This has been observed in cancers of the lung, colon, and bladder, where sing1e-base-pair substitutions in the DNA sequence have been de scribed. What these changes in the malignant cells imply with respect to the susceptibility of the host is not yet clear. Recently, for example, Hall and his colleagues (44) have examined the relationship of nine such loci to the susceptibility to breast cancer; the specific loci were HRAS, KRAS2, NRAS, INT2, MYB, MYC, MOS, RAFI, and ERBA2. Linkage analyses failed to suggest that polymorphism at any one of these loci was associated with susceptibility, and these authors, therefore, conclude that these oncogenes are not the primary sites of alterations leading to breast cancer. This analysis could not, of course, exclude the possibility that alterations at these sites were involved in tumor progression, nor does it follow that the situation with regard to breast cancer will obtain for other malignancies. Second, the relationship between chromosomal change and oncogenesis has also been extended by the finding on chromosomes of fragile sites close to the location of known oncogenes (see e.g. 81 and 105). Many such sites appear to be targets for DNA-damaging agents, such as ionizing radiation. This has led to the suggestion that individuals with rearrangements at these fragile sites may bave an increased predisposition to breakage that is heri table, manifesting itself in an increased risk of familial cancer. Whether this is so remains to be established; however, Mules and her colleagues failed to find an increased risk of cancer among the relatives of leukemic patients with chromosomal rearrangements at rare, heritable fragile site locations in their malignant cells (86). Nevertheless, increasingly it appears that most tumors, possibly all, have specific karyotypes and that these karyotypes are often predictive of the course of malignant growth and the response of the tumor to therapy. Third, a variety of genetic mechanisms have recently been implicated in the development of colon cancer. These include localization of the familial polyposis coli gene to chromosome 5 (75), characterization of ras-gene mutations and a series of chromosomal deletions in colon cancers ( 124), and the identification in tumors of specific point mutants in the gene coding for transformation-associated protein p53 gene in conjunction with chromosome 17 deletions (8). In the latter study, two tumors were investigated. Although they both had a point mutation in the p53 gene, the specific mutations and reSUlting amino acid substitutions were different. Even though the process is extremely complex, these studies document that the genetic mechanisms implicated in rarer cancers may also play a part in this more common cancer, and the vast heterogeneity observed may be the result of fewer basic mech anisms than had been previously thought.

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Diabetes Diabetes, one of the more protean diseases, exemplifies the potential in terfaces between genetics and public health. It has long been known that diabetes aggregates in families. The recognition of two main forms of this disease, namely, insulin-dependent and non-insulin-dependent diabetes mel litus (IDOM and NIDDM, respectively), has not changed the perception of aggregation. It has led, however, to clear differences in suggested genetic etiologies. Paradoxically, 100M demonstrates much weaker familial aggregation than does NIDOM, but it is for lODM that more basic genetic mechanisms have been proposed (78, 102). In large measure, the driving force behind the genetics of IDDM has been the demonstration of its clear association with the HLA haplotypes DR3 and DR4 (recently reviewed in 119). It has been proposed that at least one IDDM susceptibility locus is in the HLA-D region (35). Interestingly, among American Blacks there is a strong association between IDOM and the HLA-B8 and B15 haplotypes (101). In spite of the implied genetic factors, concordance of IODM in identical twins is less than 50% and is approximately equal to the risk in fUll-siblings that share both DR3 and DR4. When siblings share neither DR3 or DR4, the risk is less than 1% (35). No genetic model has yet been found that explains the various empiric recurrence risks. In contrast to IODM, no strong associations with particular genetic markers have been identified for NIDDM, but familial aggregation is much stronger. Concordance of NIDDM for identical twins is greater than 90% and empiric risks in first degree relatives are similarly higher than is the case for IDDM (35). Here, too, this stronger familial aggregation has not yielded to explana tion by straightforward genetic models. This is not to say that additional infonnation is lacking that implicates genetic factors beyond simple familial aggregation, which can result from both shared genes and shared environ ments. Indeed, epidemiologic and genetic studies of populations have pro vided 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 Indians of Arizona (63). Genetically admixed groups having native American Ancestry, such as Mexican-Americans, have been shown to have rates of diabetes that are proportional to the degree of Amerindian ancestry (36, 46, 47, 115, 116). That the pattern is consistent among various Amerindian and admixed groups across widely differing environmental strata leads one to presume a genetic mechanism (126), although it is difficult to preclude all other causal mechanisms such as responses to the childhood environment, including age-dependent con sequences of infection and adaptation to diet early in life (9). The implied genetic role in NIDDM and description of the numerous



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metabolic pathways 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 carbohydrate metabolism and include the insulin gene, insulin-like growth factors, insulin receptor, and the numerous glucose transporters. Rare mutations in the insulin gene are known to produce abnormal insulins and can lead to diabetes (45), and though they have little direct public health impact, they identify targets for investigation. Initial reports of an association of the 5'hypervariable flanking region of the insulin gene led to attractive scenarios of common genetic variability con tributing to diabetes susceptibility (103), but the results have not held (10). Recent work among diabetic Chinese Americans (133) that examined vari ability at the above genes and also several lipid-related genes, identified several significant, albeit small, associations. Variability at the insulin recep tor, apolipoprotein (apo) B, and the apo A-I/C-UI/A-IV structural genes was implicated ( 133). Of particular interest in this work was the attempt to take account of association in different obesity classes. It was shown that possibly 8% of the increased risk of overweight individuals over base-line could be explained by variability in the apo A-I/C-III!A-IV region. The gen eralizability of these results awaits confirmation in other population or eth nic groups. Lack of generalization to other population groups will not necessarily imply that the results among Chinese American diabetics are spurious. Epidemiolo gy and public health have clearly established that disease impact is not consistent across populations. Likewise, genetic studies have repeatedly demonstrated heterogeneity of gene frequencies among populations, so it is reasonable to expect to find heterogeneity of associations. This underscores the need for caution in inferring etiology from associations and requires that public health measures account for population heterogeneity and alternative explanations. An illustration of the problem is the distribution of Om haplo types among Pima and Papago Indians. Knowler and colleagues (65) clearly demonstrate that an apparent strong association of a particular haplotype with NIDDM is explained by admixture. That is, the haplotype is a marker of Amerindianness, which happens to be highly correlated with diabetes risk. Hence, ignoring population genetic structure would have led to erroneous inferences. In addition to studies of disease and marker association, genetic linkage analysis can provide alternative insights into the role of specific genetic loci and disease. Investigations of Caucasian (30) and Black (19) pedigrees that used 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 (19). In both studies, a variety of model-dependent and model-free genetic approaches were used and yielded equivalent results.


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Similar conclusions were drawn for the insulin receptor locus (19), but it was this locus that was implicated in the association studies above (133). Several factors may account for the seemingly different results. First, linkage is not synonymous with association, nor does association imply linkage (123). Second, the association study found that there were seemingly protective haplotypes that resulted in reduced diabetes risk, hence the focus was differ ent. Third, these are quite different populations. The themes above will undoubtedly be expanded in the 1990s and will have varying impacts on public health. Obviously, our understanding of metabolic and molecular events will only increase, but with the concomitant realization of their complexity. With increased description of the events, there should be an enlarged understanding of regulatory events. Whereas presently our focus is necessarily on structural loci, the greatest potential will lie in examining gene regulation. Heterogeneity within and between populations will continue to be troublesome and underscores the need for (a) careful definition of the population of inference and (b) use of more standardized protocols across population groups. Two other areas of study that will become increasingly important relate to complications and interventions. Discussion here has been limited to the simple presence or absence of diabetes, but it is the understanding of the development of complications and appropriate intervention strategies that will have the greatest impact on public health. In large measure, both areas require longitudinal follow-up of the general population of diabetics. Studies such as those among the Pima Indians (77) or in Framingham (1) have demonstrated the power of longitudinal studies to identify causative factors. In many instances they identify premonitors of disease such as obesity that are present long before the development of clinically overt disease. This long time lag will only increase the difficulty with which efficacious strategies can be designed, invoked, and assessed. A particular strength of genetics in this regard is the focus on pedigrees. Generally, intervention strategies are dis cussed in terms of popUlation versus high risk strategies of intervention (69). For diseases such as diabetes with strong familial aggregation and a long pre-disease state, it may be that family based intervention strategies will offer the greatest potential. Educational and other noninvasive approaches may prove extremely powerful in family-based settings where the unit of interven tion is a high risk pedigree (see also 55). A last comment regarding the interface between the molecular approaches and intervention relates to genotype by environment interaction: Although 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 manipulation (including medication) and yield results that surpass expectation based on association studies.


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Obesity

Obesity is significantly associated with the onset of non-insulin-dependent diabetes mellitus (127), premature myocardial infarctions and hypertension (96), cholecystitis and cholelithiasis (2, 48), cancer of the corpus of the uterus (131), gout (132), and possibly fatal cancer of the prostate (114). Adiposity is second only to age as a risk factor for NIDDM, and it is similarly important in hypertension (95), although in hypertension there are apparently sex differ ences in the association of the distribution of subcutaneous fat with car diovascular risk factors (51). Obesity threatens health in other ways as well; for example, obese hypertensives, particularly males, are more resistant to antihypertensive medications (82). Hyperinsulinemia and insulin resistance are more common among the obese, particularly those with a centralized distribution of body fat (61, 70). Response to dietary cholesterol is inversely correlated with body mass index; hyperresponders are invariably leaner (58). Similarly, obese individuals commonly have lower caloric intakes than do non-obese individuals. Moreover, body weight and fatness have been shown to be potential confounders in the assessment of the risk of physical activity (3, 73). We have recently reviewed several aspects of the genetics of obesity (109) and touch only on a few of the major issues here. Genetic variation has been implicated in the origins of obesity through a variety of approaches. These include comparing similarities in weight be tween monozygous twins and between dizygous twins (32); examining cor relations between foster children and their adoptive and biological parents (5, 6, 117); and investigating pedigrees (see 15, 84 for reviews of these st�dies). Ostensibly, these studies share a focus on weight, but they often differ in the ages at which weights were measured and seldom has the process of weight gain been considered. Also, excess body weight is only one measure of risk for chronic disease. Studies need to examine the distribution of body fat as well (42, 43, 57, 61, 100). In this regard a variety of different classification schemes have been used, ranging from simple silhouettes to complex statisti cal procedures. Studies of the genetics of body fat distribution are infrequent, as are studies that have considered the tracking of weight or fat distribution. In spite of differences in measures and approaches that have been used, there is consistent evidence that some one-third of the variability in fatness among individuals is explainable by genetic factors (15, 16, 84, 106). Furthermore, at least among children, there is evidence that more than 50% of the tracking correlation in weight is attributable to genetic effects (50). As with other chronic disease measures, only recently have specific loci and metabolic events been identified wherein the impact of genetic variability can be directly tested. Over the past decade or so, a greater role of the so-called satiety hormones or brain-gut peptides has been elucidated. Cholecystokinin and bombesin, for


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example, are peptides found in the gut and in the central and peripheral nervous system; both are known to inhibit food intake after peripheral and central administration. Cholecystokinin clearly plays a role in integrating the intestinal phase of digestion, and its effects on satiation are specific, although the mechanism of the effect is not fully known. It has been conjectured that the satiety effect is due to the activation of vagal afferent fibers that inhibit the central control of feeding, and that cholecystokinin either acts directly on numerous vagal receptors or indirectly through a gastric smooth muscle effect (99, 112). Little has apparently yet been done with respect to most of these hormones toward assessing the role of genetic factors in their determination and variability, although the genes responsible for cholecystokinin (27), glucagon (128), and somatostatin (41) have been cloned and sequenced. A second candidate for investigation in the role of obesity and fat patterning is sex-hormone-binding globulin (SHBG). SHBG is a genetically controlled protein whose functions are not fully understood. A significant inverse correlation between SHBG and body weight has been found (26). Results consistent with this inverse correlation have also been reported from com parisons of obese men and women with lean controls (68), and there is some evidence of an association with the distribution of body fat as well (31, 97). Two other systems have also been identified as candidates and are intrigu ing not so much for their direct effects on obesity as the glimpse of the metabolic relationships between obesity and other chronic disease problems that they provide. First is the apparent functioning of the enzyme lipoprotein lipase as the "gatekeeper" for the entry of lipids into the cell and a role in balancing energy requirements and storage needs (130). Lipoprotein lipase is regulated by nutrient intake and hormones and has been postulated to play a key role in both obesity and atherosclerosis (130). It is also found to be decreased in adipose tissues of diabetics (37) and is induced by insulin (52). The cDNA sequence of lipoprotein lipase is known (130) and it is a member of multigene family (67). Second is the role of several red blood cell mem brane ionic pathways. They include (a) the Na-K pump, an active pathway that is inhibited by ouabain, a glycoside obtained from the wood or seeds of several plants; (b) the sodium cotransport system, a passive pathway inhibit able by furosemide, a complex anthranilic acid often used as a diuretic; (c) the sodium-lithium countertransport system, another passive pathway inhibited by phloretin, a glucoside derived from the bark of many of the Rosaceae, and finally, (d) the "leak," a minor pathway that seems to reflect a random loss of the ion in question. Each pathway has been shown to be associated with some form of ill-health and to be under a degree of genetic control. For example, elevated sodium lithium countertransport is more frequent in individuals with essential hypertension compared to normotensive persons (121, 122), and it has been shown that about 50% of the normal variability between individuals



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is attributable to the segregation of genetic factors (14). Studies in the obese mouse, a common animal model for obesity, have established that the homozygous obese mouse has reduced levels of sodium-potassium ATPase (134). Human obese subjects have been shown to have an approximate 22% reduction of sodium-potassium pump units compared with non-obese controls (23-25, 62). Obviously, the origins of obesity and fat patterning are complex, with numerous opportunities for genetic variation to impinge on the processes involved. Few studies have examined more than one of the numerous interact ing factors. Collectively, the number of measurable genotypes with apparent effects upon obesity has increased at a pace that warrants consideration of an analysis based upon the role of specific genotypes. Furthermore, although obesity appears to be a characteristic of all human populations under appropri ate circumstances, there is marked heterogeneity in its frequency and impact. Among populations having extremely high prevalences of obesity are native American Indians (95); Nauruans, Samoans, and other indigenous inhabitants of islands of the Pacific (60, 135); and many admixed groups such as the Mexican-Americans of the United States (85). As with diabetes, prevalence of obesity among Mexican-Americans parallels the degree of Amerindian admixture and further supports the role of genetic mechanisms (126). Of particular interest with regard to the role of genes are the temporal trends that have occurred in obesity frequencies among high prevalence groups. Obesity, and also diabetes, have increased markedly in frequency in the past few decades. Lifestyle changes undoubtedly explain some of the increase, but not all populations have responded to lifestyle changes to the same degree, thus suggesting a genetic background that is especially suscepti ble (64, 118, 126). Even though obesity poses serious public health consequences in its own right and affects nearly every other chronic disease problem as well, body mass is generally treated as a concomitant for which data should be adjusted. Such treatment ignores the biological importance of the interaction between various risk factors and may lead to underestimation of the role of genetic factors. For example, it has been shown that 30% of the full-sibling correla tion in systolic blood pressure can be attributed to the familial aggregation of body weight (50). It would seem that body mass is a measure to be utilized rather than simply adjusted away.

THE 1990s Speculation on the future of genetics in public health, even in the short run, is an intrepid, if not a presumptuous act. Progress in genetics, particularly at the molecular level, over the past decade has been so rapid that its impact still


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awaits a measured assessment. Nonetheless, some aspects of the future require no special prescience. Technological advances promise a full sequenc ing of the human genome in the decade ahead, but understanding of the role of much of the genetic variability that will stand revealed will proceed more slowly (80). Knowledge of the sequence of a given gene does not establish its function or its regulation; the latter information will emerge only through a laborious dissection of the processes that culminate in disease. Furthermore, multiple sequences of disease-associated loci will be required to determine the extent of genetic heterogeneity. Even seemingly homogeneous diseases such as PKU and familial hypercholesterolemia have revealed tremendous heterogeneity at the DNA level (40, 110). Gene therapy, which has received so much attention and will undoubtedly be useful in some diseases, will not be a panacea. It is difficult to see what role it could play in diseases that stem from an interaction of genetic and environmental factors and in which some risk is associated with every genotype. A more likely scenario is that different treatment efficacies will be obtained and exploited in different genotypes. It has already been demonstrated that genetic variability at the apo E locus is associated with differential response to probucol (92). There is no reason to doubt, however, that these new developments will give molecular epidemiol ogy a substance that it has not previously had, and that techniques such as the polymerase chain reaction, which make possible the amplification of amaz ingly small amounts of DNA, will see widespread application both at the individual and population level. Genes are not static in their action, and the need to know how their action changes with time looms progressively larger in our understanding of disease. We have undoubtedly been too preoccupied with the near events to discern adequately the etiological roots of disease. As the evidence builds that many chronic disorders have their origins in childhood, we will see greater empha sis upon the nature of gene-environment interactions in the earlier years of life and the interactions between different risk factors. This will increase the need 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 (79), or among putative "high-risk" individuals. We will see the family more frequently become the unit of intervention, particularly in dis eases such as non-insulin-dependent diabetes and obesity, as noted above. As Childs has cogently argued (18), disease is as much an expression of in dividuality as any other human characteristic, and although tailoring public health measures to the individual may be impracticable, this ideal would be more nearly approximated if efforts were directed toward the family. Studies of host susceptibility to disease, particularly those of viral or putative viral origin, will increase in number and sophistication. They will seek to determine the role of genes in the susceptibility of the host to disease,



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the course of disease once infection occurs, and the response to therapy. For example, viewed globally, hepatocellular carcinoma is one of the world's most common cancers, and it has been estimated that in 75 to 90% of such instances the hepatitis B virus is the etiologic agent. It is known that hepatitis B virus DNA is almost universally incorporated into the genome of hepato cytes of individuals with chronic infections as manifested by a positive response to HBsAg; yet other individuals apparently eliminate the virus and develop protective antibodies (anti-HBs). Why this should occur is presently unknown, but there is ample basis for speculating that this variability in response to the virus is genetic. Similarly, we can anticipate further research on genetically determined variation in response to environmental carcinogens, mutagens, and terato gens, and to pharmaceuticals-what has been called pharmacogenetics (123). We hope that the 1990s will see the means to study genetic variation in the regulation of metabolic processes. Now we are largely limited to examining variability at genetic loci that code the structural form of proteins, presuming that variation in these genes alters risks. Obviously regulatory genes would be a more fruitful area of inquiry, and the sequencing of the human genome may provide the necessary insights into the location and organization of such genes. As our understanding of the genome increases, we anticipate a beginning to the unraveling of the complicated processes that lead to mental health prob lems and behavior. There are clear genetic roles in the determination of disorders such as schizophrenia and bipolar disease, but the inability to identify the specific loci involved has made interpretation and prediction difficult at best. Linkage analyses in which molecular markers are employed, however, are beginning to identify and exclude candidate loci that may contribute to the occurrence of schizophrenia and other psychiatric disorders (59, Il l ). Like other diseases mentioned in this review, heterogeneity seems to be the rule. Although linkage of schizophrenia was shown with a locus on chromosome 5 in a small group of Icelandic and English pedigrees (111), this same locus has been excluded as a candidate for schizophrenia in other population groups (28, 59). The ability to identify specific groups that may share a common etiology should lead to better definition, understanding, and prediction of the broad classes of mental health problems (71). Will genetic screening become a routine element of the standard employ ment examination, as tests for vision and hearing now are? Would such screening be wise? Holtzman (54) has argued that there is no retreating from the use of genetic tests, if not in an occupational setting then in the practice of medicine. But should such testing be at public expense, and might not other programs contribute more to public health? Moreover, how is the public to be assured of the requisite validity and reliability of the tests, of equity in access


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to such tests and ensuring care, and of the knowledge to use the information revealed by testing wisely? Patently, answers to some of these questions transcend conventional public health concerns, if not in kind then certainly in degree. These are societal issues that impinge on traditional notions of individual liberty, and they can ultimately be answered only by an informed public. Arguably the biggest barrier to a greater role of genetics in public health will continue to stem from differences in the perspectives of epidemiologists, geneticists, clinicians, and molecular biologists. For example, epidemiolo gists appear to thrive on model free hypotheses, geneticists on precisely the opposite. As Murphy (87) has stated, epidemiology prospers on badness-of-fit tests, the rejection of the null hypothesis, whereas genetics prospers with goodness-of-fit tests, the capacity to model a set of events suitably. Whether a successful accommodation between the different perspectives will be achieved remains to be seen. If it is to come, education will be the avenue. Few Schools of Public Health, however, offer genetics as a part of their curriculum, and we are aware of none in which it is required. Similarly, few geneticists are familiar with the methods of epidemiology or the nature of public health practices. Literature Cited 1. Abbott. R. D., Wilson, P. W. F., Kan nel, W. B., Castelli, W. P. 1988. High

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Setting objectives for public health in the 1990s: experience and prospects.

Health and the environment in the 1990s.

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