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THE GENOME:: NUTRITION AND HUMAN VARIATION iA, `,o Motulsky This paper presents an overview of the role of genetics in nutrition and nutritional policy. It includes discussions of human individuality and how it is controlled by genetics, some examples of common and rarer diseases in which genetics plays an important interactive role, and some of the problems of-public policy raised by our current knowledge of genetics and how these problems will compound as our knowledge of genetics increases over the next 10 to 20 years. HUMAN lIARIABILITY Human variability, or genetically controlled variability, is very common. All people who are not twins look different; clearly, this is genetically controlled. We also tend to resemble our relatives more than we do our nonrelatives, and these similarities in physiognomy are controlled by genes. The similarity in physiognomy is also carried over in the ways that people, for example, hold their hands or~make gestures. Thus, aspects of behavior that we do not ordinarily think of as being under genetic control are, in fact, controlled by genes. Although we do not know which genes are involved in physical or behavioral resemblance, we do know that genes are involved. Over the past 20 years or so, internal genetic variability has also become apparent. For example, blood groups and various enzyme and protein types are now known to be genetically determined. The HLA variants also show tremendous genetic variability. More recently, chromosomal variants have shown considerable variability at the DNA level. Since most human DNA does not code for protein, the variability of UNA is usually not expressed 32

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phenotypically. However, such variability can be used, and is being used increasingly, as a marker for genes lying next to these DNA variants that are expressed. What this research indicates is that if we take just a few markers (but not DNA markers or HLA markers), we can show that the chance that two randomly selected people will have the sane genetic type becomes extremely small. If we then add all known markers to the equations, we can establish mathematically that all people, except, of course, identical twins, are unique internally in respect to their various genetic markers. The question therefore arises: How important is this variability in nutrition and health? To answer this, we must consider the nature of internal variability. If we assume that a gene is fully expressed and look at those that carry the gene and those that don't (i.e., homozygotes), there are found to be two distinct populations or distributions. If we assume that some people are heterozygotes and if we can distinguish between the two homozygotic and one heterozygotic populations, then there will be three separate distributions or curves. Since many genes interact with a variety of other genes (the so-called polygenetic situation), however, we most often get a single Gaussian distribution curve that is very common for all kinds of biological phenomena. This can be observed in the case of a very simple genetic interaction of just two pairs of additive genes. For example, the variability of enzyme levels within the normal ranges often has a simple genetic basis, because different alleles at a Gene locus that specifies one structure or a given enzyme may be associated with slightly different mean enzyme levels. Thus, the widely variable quasi-Gaussian distribution of activity for a given enzyme in a population may be the result of few overlapping curves, each of which is characteristic of its underlying allele. . ~ . .. . . _ . ~ What is the relevance of this variability to nutrition? As is well known, there are many intrinsic processes of nutrition. These include absorption of nutrients, as well as their distribution, catabolism, uptake by receptors, transport across cells, storage, and excretion. It would therefore be surprising if the high degree of variability in the human biochemical makeup did not affect these processes, thereby influencing nutritional requirements and interactions. 33

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Another point to consider is common variability. Several hundred inborn errors of metabolism, in which a variety of enzymes are absent or deficient, are known to us; many of these are known to lead to gross abnormalities in the organism. For example, phenylketonuria (PKU), a relatively common condition marked by the absence of the enzyme phenylalanine hydroxylase, occurs in the homozygous state in about 1 of 12,000 to 1 of 15,000 people. This disease, which leads to mental retardation if unchecked, can be prevented by restricting phenylalanine in the diet. It takes a double dose of the gene to produce PKU (as it does for most inborn errors of metabolism), and that is why recessive diseases such as PKU are relatively rare. From what we know of genetic arithmetic (i.e., the Hardy Weinburg Law), however, for every rare homozygote in the population, there are many heterozygotes or carriers of the gene. Thus, for an autosomal recessive disease like PKU in which 1 in 12,000 people is affected, we can estimate that approximately 2% of the population carry the gene. What, then, are the implications of this common carrier state for nutrition and health? In general, people who are affected with such inborn errors have very little to no activity of the involved enzyme, while normal people have about 100% activity and carriers have about 50% activity. Under most conditions, a 50% level of enzyme activity is sufficient for adequate function and carriers remain in good health. Under conditions of growth, stress, illness, or malnutrition, however, a 50% level of enzyme activity may not be sufficient to maintain health, and specific abnormalities related to the underlying enzyme activity could result. Familial hypercholesterolemia is an example of how a heterozygotic or carrier state for a metabolic condition can cause a relatively high disease rate. Another example of variation that affects food likes and dislikes, and, thus, probably nutritional status, is phenylthiocarbamide (PTC) nontasting. PTC nontasting is an example of a common monogenic trait that makes a significant proportion of the affected population unable to taste bitter substances. There are also less well-studied examples, such as variability in the ability to taste artificial sweeteners. Such subtle differences undoubtedly affect food preferences. 34

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Genes do not act in a vacuum, and the action of a specific gene may depend not only on other genes but also on the environment. This principle is well illustrated by the field of pharmacogenetics. Certain inherited enzyme variants are harmless per se but they may cause untoward effects in the presence of a drug that requires the normal variety of that enzyme for its inactivation. In such cases, the presence of the enzyme variant by itself without the drug or the administration of the drug to people with the normal enzyme levels may cause no harm. If the drug is given to carriers of the enzyme variant, however, a drug reaction may ensue. Examples of this phenomenon include hemolytic anemia from glucose-6-phosphate dehydrogenase (G6-PD) deficiency, prolonged apnea from pseudocholinesterase variation, and various drug reactions associated with defective acetylation of drugs such as isoniazid. EXAMPLES OF THE INTERACTIVE ROLE OF GENETICS The concept of pharmacogenetics can also be applied to ecogenetics, that is, the interaction of specific genetic traits with any environmental agent to produce a given effect. Some ecogenetic examples of nutritional interest include (1) the development of gastrointestinal symptoms upon drinking moderate quantities of milk among the many individuals with genetically determined lactose intolerance; (2) the development of hemochromatosis in susceptible individuals who consume moderate dietary levels of iron; and (3) the development of hypertension in genetically predisposed people who migrate from a less developed, primitive environment to a more industrial Westernized environment. For example, lactose intolerance, a common trait in which there is a persistence of the lactase enzyme in the intestine, is an excellent example of a simple genetic trait that affects absorption of commonly used foods, namely, products containing lactose. At the time of birth, all humans (as all other mammals) are able to make and use the intestinal enzyme lactase to break down the main constituent of milk, lactose, into glucose and galactose. In most humans, the ability to digest lactose disappears after weaning, but some individuals do not lose this ability and have persistent intestinal lactase activity (Lisker, 1984~. Symptoms in lactose 35

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malabsorbers occur because undigested lactose in the gastrointestinal tract is decomposed by bacteria, causing bloating, diarrhea, intestinal rushes, flatulence, and even nausea and vomiting in severe cases. The lactose persistence is controlled by a gene (L) that may occur in the heterozygote (L1) or homozygote (LL) state. People who do not carry the L gene, and who therefore cannot digest lactose after weaning, are homozygotes (11) at this locus, which is the usual status for most of the world's population. Milk drinking does not induce lactase activity in those who no longer have this capacity, nor does lactose restriction reduce-the intestinal lactase activity among those who never lost it. Lactose absorption (L1 or LL) or malabsorption (ll) is an inborn trait. . . Acute or chronic gastrointestinal disease may cause secondary hypolactasia among individuals with persistence of lactase activity, but intestinal lactase activity returns after the illness. Members of most populations have hypolactasia of the genetic variety. Only people from central and northwest Europe and from areas in Africa with a long history of dairy activity have high frequencies of persistence of lactase activity. Presumably, the gene for lactase persistence had a survival advantage in cultures with dairy activities, and over the generations it has increased in frequency because individuals who were able to absorb milk as children and young adults were either more fertile or less likely to die. Another example of how genetic variation influences nutrition is the condition hemochromatosis. Those people who are affected are homozygotes for a gene that facilitates increased iron absorption and is carried on the short arm of chromosome 6, which is closely linked to the HLA-A locus. The homozygous state affects about 1 of 600 to 1 of 1,000 individuals in the United States and Western Europe, indicating that about 10% of the population is a heterozygote for or carrier of the condition. Clinically apparent disease is more common among males, since females can eliminate some excess iron in their periodic menses. Since iron deficiency is common among the population at large, supplementation of flour with iron has been recommended by public health authorities and is practiced in Sweden. The onset of clinical hemochromatosis in homozygotes presumably would be hastened by such a process. However, since the proportion of people with the homozygous hemochromatosis 36

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genotype is at most 1 in 500, some observers think that the merits of iron supplementation benefit a much larger fraction of the population and outweigh the damaging effects of excess iron in homozygotes. A crucial issue in this connection is related to the iron absorption status of the very common hemochromatosis heterozygotes (i.e., close to 1 in 10 people). However, current data suggest that while liver iron stores are somewhat increased among male heterozygotes as they get older, there is no evidence that heterozygotes are at risk for clinically apparent iron toxicity. Another example of ecogenetics is that of high blood pressure and salt. Hypertension is an ecogenetic trait in that populations from less developed locales have little or no hypertension. High blood pressure develops in some migrants to a Western-type environment when the diet includes a high salt intake. Populations of African origin in the U.S. have a higher mean blood pressure and a higher frequency of hypertension than those of European origin. ~ ~ ^^ ~ ~~ ~ recently Discovered ul~terences between black and white hypertensive populations include the absence of elevated red blood cell sodium and lithium countertransport in blacks--a finding that is also common among white hypertensives. This transport trait appears to be under monogenic control. This and other evidence suggests that hypertension is a heterogenous entity with different genetic mechanisms. The fact that blood pressure levels are under strong genetic control is shown by studies in families, adopted children, and twins. Evidence for the role of sodium in the causation and maintenance of high blood pressure is also good. On a population level, the frequency of high blood pressure in different populations is related to their average sodium intake. However, sodium loading does not cause elevation of blood pressure in all individuals, and sodium restriction lowers blood pressure in many, but not all, hypertensives. Salt restriction has been advocated to reduce the frequency of high blood pressure, but it may not be helpful for the entire population. Currently, we lack clinical or laboratory criteria to differentiate those individuals who are salt resistant from those who are salt sensitive. Another trait that is important for public health is obesity. Obesity clearly is related to food intake, 37

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although a variety of studies indicate that food intake alone does not explain all the variation in obesity. Studies done in twins have been useful in this regard. Assuming that all human variation is genetic, we would expect correlations between identical twins who share 100% of their genes to be 1.0, while we would expect it to be 0.5 between unidentical twins, who share half of their genes. In the case of body mass index, the correlation for identical twins is 0.8, while that for nonidentical twins is 0.42. This suggests that genetics plays a major role in the risk of obesity. In addition, studies have shown that children seem to have a body weight that resembles that of their biological parents more than that of their adoptive parents. This again suggests that genetic factors are involved. The exact mechanisms that make some people obese and others not are not yet known. Lastly, I would like to consider how genetics modulates hyperlipidemia and coronary heart disease. Both genetic and environmental factors influence a variety of different lipid parameters that are involved in hyperlipidemia and heart disease. Cholesterol levels in serum as well as low high-density lipoprotein levels, high apolipoprotein B levels, and low apolipoprotein Al levels have all been implicated as risk factors for coronary heart disease. Various alleles at the apolipoprotein E locus have a significant effect on raising or lowering cholesterol and apolipoprotein B levels. Monogenic defects causing hypercholesterolemia (i.e., familial hypercholesterolemia due to a low-density lipoprotein receptor defect) have been carefully defined, whereas the evidence for single-gene inheritance of some other lipid abnormalities has been less certain but suggestive. Regardless of the genes involved, genetic factors of some sort play a role in most of the hyperlipidemias. A common condition known as familial combined hyperlipidemia appears to be transmitted as a monogenic autosomal dominant trait and is usually associated with elevation of apolipoprotein B levels. Various DNA markers of the apolipoprotein loci have been associated with hyperlipidemia and with coronary heart disease but the results have not always been consistent. Considerable research work is being carried out in these areas and is likely to clarify the exact contribution of genetic factors to hyperlipidemias. 38

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PROBLEMS OF PUBI POLICY __ GENETICS What, then, are the nutrition policy implications of genetic variability? Given the probable effects of biological variability on nutritional requirements and chronic disease, we should first ask whether different dietary guidelines might be required for different populations or individuals. If variability is small and it can be overcome with general nutritional guidelines that are easy and acceptable to everyone, then one can ignore genetic variability-and make a single recommendation for everyone. For example, we know that there is genetic variability in caries susceptibility, but fluoride is still given to everyone anyway. The situation becomes less clear when we know that a general guideline helps many but may hurt a few. The fortification of foodstuffs with iron, increasing the risk of hemochromatosis in susceptible heterozygotes, is one such example. Another point bears on this issue of individual versus population recommendations. Some argue that a lowering of the cholesterol level of Western populations by dietary modifications would substantially reduce the frequency of coronary heart disease, regardless of genetic variaticholesterol level from 226 to 210 mg/dl, as might be achieved with dietary modification, would reduce the absolute risk of mortality from coronary heart disease only slightly. However, a small reduction in absolute risk for any individual may have a major effect when it is translated into the very large number of individuals that constitute the population. This is the so-called prevention paradox named by the British epidemiologist Geoffrey Rose. In a hypothetical example, assume that a person can reducetuation becomes less clear when we know that a general guideline helps many but may hurt a few. The fortification of foodstuffs with iron, increasing the risk of hemochromatosis in susceptible heterozygotes, is one such example. Another point bears on this issue of individual versus population recommendations. Some argue that a lowering of the cholesterol level of Western populations by dietary modifications would substantially reduce the frequency of coronary heart disease, regardless of genetic variati the risk of having a myocardial infarct in a given time span from l in 80 to 1 in 100 by altering his or her diet. If these figures were applied to lOO,OOO individuals, the expected 39

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i frequency of 1,250 myocardial infarcts (1 in 80) would be reduced to 1,000 heart attacks (1 in 100~. This reduction of 250 heart attacks per 1,000 individuals at risk would be of substantial public health importance Although little is known about the effect of nutrition-genetic interactions on lipids, however, it is likely that some individuals are sensitive to dietary lipids while others may be resistant. The roles of the low-density lipoprotein receptor, structural variation in apolipoproteins B and E, the regulation of hepatic apolipoprotein B synthesis, and many other factors need to be studied to resolve these issues. Public health policies have largely ignored genetic variation and have used an "average" human being in their formulation. Thus, nutritional recommendations have usually been set to provide a sufficient amount of a nutrient even for those with the highest requirements. With relatively small variation for a given nutrient, such a nolicv annears sound. Also, if special dietary requirements affect a few individuals with inborn errors of metabolism, policy recommendations can ignore such outliers since these individuals can be identified and will be treated by physicians. In many instances, however, the true extent of genetic variation is still unknown. We are indeed all different. We taste things differently; we smell things differently and as noted earlier, it is likely that these differences influence the nutritional metabolic processes, requirements, and interactions that can lead to chronic disease. Judging from the frequency of genetic variants in enzymes and proteins and their effects on enzyme activity, significant variations in nutritional requirements or in genetic-nutrition interactions may often exist. Thus, while population-based guidelines may, for the most part (at present), be sound, each nutritional topic must be considered on its own merits. In addition, since there are sizable racial or ethnic differences in disease frequencies, it is conceivable that a recommendation for one group of the population may need to differ from that for the other groups. Such differences among races may raise difficult policy questions because they can easily be misunderstood. However, there are precedents from a nonnutritional setting. Ashkenazi Jews are already 40

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screened for Tay Sachs disease, Mediterraneans and Southeast Asians are screened for thalassemia, and blacks are screened for sickle cell disease and trait. Under ideal circumstances, we could tailor dietary recommendations to each individual, depending On his or her genetic makeup or susceptibility. Although we have an inkling of the extent and type of human variation, however, much more work is needed to elucidate the descriptive, metabolic, and biochemical bases of this genetic variation. Sensible dietary recommendations can be made for the general population, although we must not ignore individual needs. What we must remember is that the population approach and the individual approach are complementary, not opposite, and that both are necessary if we are to approach the resolution of the problems of nutritional requirements and nutritional disease. 41