THE HOST FACTOR IN DISEASE: GENETIC ASD ENVIRONMENTAL INTERACTION

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1 Part I. Adaptation in Man and Animals THE HOST FACTOR IN DISEASE: GENETIC ASD ENVIRONMENTAL INTERACTION Richard H. Osborne Sloan-Ketlering Institute for Cancer Research, New York, N. 1. The medical literature is replete with references to the so-called host factor, * giving notice of a general recognition that it takes more than a microbe to produce a disease, and that other causes are to be found in the characteristics of individual members of the population attacked, as well as in the environments in which both host and parasites, or other causative agents, find themselves (Paul, Aside from drawing attention to these salient facts and entering a plea for the early development of satisfactory methods of analysis, until quite recently there was little to be said concerning the host factor that was of pertinence to epidemiology. By bringing experimental genetics into the focus of epidemiology it is hoped that this monograph will stimulate the development of methods suitable for the analysis of differences in host resistance and susceptibility. Today there are unquestionably few who have not been indoctrinated with at least some of the basic principles of genetics and who are not fully familiar with the genetic terminology as it may apply to their particular area of interest. In this day of specialization, however, a problem arises: for within different areas of interest even basic terms and concepts take on specialized meanings that, while serving the purposes of a particular area of interest, may lead to confusion and misconception if applied in other, although intimately related, branches of the same discipline. This is exemplified by use of the terms genetic and nongenetic disease so frequently employed in biochemical genetics. To the uninitiated the terms genetic and nongenetic disease imply a contradiction of the concept of genetic-environment interaction and has the unfortunate effect of resurrecting from its long overdue grave the notion that disease is inherited. No characteristic is inherited, normal or abnormal. It is only the genetic material that is inherited, and it is this that sets the individual s norm of reaction: the limits as to how and to what degree he will react to any or all of his environmental life experiences, physical and psychological. These experiences include both the adequacies and inadequacies of the individual s nutrition, exposure to infection and contagion, the condition of his prenatal life, accidents in development, and even his age. Far from being an academic quibble, distinction between what is inherited, character or gene, is essential to our understanding of the host factor in by far the majority of disease states. At any given time, the host, the individual, is the summation of his life experiences as realized within the limits of response set by the total of his genetic endowment. The range of this response extends from the two possible extremes. At the one extreme are the single * The term host factor is used here in accordance with the popular meaning in Preventive Medicine; disease is taken to mean any impairment of health. 602

2 Osborne : The Host Factor in Disease 603 gene alterations (mutations) that impart their effects in all genetic backgrounds and in all environments (these are the situations to which the biochemical geneticist may as a shorthand convenience apply the term genetic disease). At the other extreme the effect of the genotype may be detectable only by statistical methods and then only within a limited environmental constellation. Between these extremes fall many well-known examples; a familiar one is that of erythroblastosis fetalis: an Rh-negative mother, if previously immunized by other Rh-positive pregnancies or by an Rh-positive blood transfusion, may develop antibodies to the red blood cells of an Rh-positive fetus. These antibodies may then return to attack the red blood cells of the Rhpositive fetus and result in hemolytic disease. Required is a single major gene difference, but one that will produce disease in the proper uterine environment only under a specific set of circumstances and when preceded by the prerequisite environment. These are not the only well-defined events that are required, for only 1 in 20 Rh-negative women carrying an Rh-positive fetus becomes sensitized.2 Despite the shorthand designations that geneticists use in referring to genes and equating gene action with specific genetic traits, many (and probably most) traits are affected by more than one genej3 particularly at the level of biological organization at which the majority of common disease states are defined. At this level of biological organization it is also of particular importance that the action of hereditary factors be evaluated within the context of the environments in which they are expressed. Because of the difficulties encountered in studying man in his varied and complex environment and the relative ease with which unit characters can be handled, much of our knowledge concerning the genetics of human disease is confined to those relatively rare entities that are fully conditioned by single major gene differences in the majority of normal ) environments. Xeroderma pigmentosum provides a good example: there is a simple Mendelian segregation of a major gene; homozygotes for this gene exposed to ultraviolet rays of the sun suffer severe deterioration of the skin and, possibly, death at an early age. This disease is the result of the interaction between the expression of a major gene and a normal and readily defined environmental agent. Such single gene differences, however, are not representative of the bulk of the genetically conditioned variability observed in either health or disease. Most variables of common observation are genetically comple~~-~ (for example, eye color) and are in addition subject to modification by a variety of environmental influences, as in the case of stat~re.~-~ It is in situations of this complex nature that difficulties arise and the generalized term host factor may be used to denote individual differences in disease susceptibility. The host factor, as this term is commonly employed, is not synonymous with genetic factor, for included are other features-phenotypic features such as nutritional status and body temperature. These characteristics are the result of genetic-environment interaction; consequently, the concept of a host factor does not distinguish between determinant and effect or genotype and phenotype. This is essentially a descriptive term and, for the purposes of objective analysis, it is necessary to distinguish between genetic and environmental components of the variability

3 604 Annals New York Academy of Sciences described. By the application of genetic methods of analysis this is possible, and considerable progress has been made in a number of instances where both a definable genetic factor and a causative agent or specific environmental situation are prerequisite to the disease process. Some examples of these in man and other animals are presented in the papers following. In many other instances, of course, it has not yet been possible to partition the host factors in such a way as to provide satisfactory explanations for observed differences in individual susceptibility to disease, for example, in many forms of cancer or cardiovascular disease, both of which are important subjects of epidemiologic investigations. When a disease, as it is clinically described, fails to show clear-cut Mendelian ratios within affected families or to have simple causative explanations that always result in a comparable impairment of health in all individuals subjected to its influences, the usual procedure is to single out the most likely diagnostic criterion for genetic study. A good example is that of blood pressure] which is of proved value in the description of disease and has been frequently made the object of genetic investigation. Clinical evaluation of the measured level of the blood pressure is based upon population norms and the total of the circumstances in which a particular reading or set of readings are obtained. In the early itudies of this variable, attempts were made to take clinically defined ranges of normal and abnormal readings as discrete traits. Studies by Pi~kering,~ Miall and Oldhani, O and others have since shown that blood pressure is a continuously distributed variable and that whereas the measured level of the blood pressure may have a genetic component of variability, environmental influences such as nutritional status and stress are also of great importance. In a recent collaborative study Osborne et al.* employed the twin-study method in the analysis of blood pressure. Twins provide a particularly sensitive technique for partitioning the hereditary and environmental components of variability of such attributes. In that study of disease-free adult twin subjects, basal blood pressure gave a very poor indication of a genetic component of variability. The same was true when casual blood pressures were employed. Further interpretation of these data led to the conclusion that there are genetic influences that affect blood pressure readings but that blood pressure measurements per se poorly describe the genetically conditioned variables. (A full report of this study has been prepared for presentation elsewhere. I cite it here only to provide an example of the character abstraction that may be represented by such critical variables as the measured level of the blood pressure.) The fact that medically useful and reproducible measurements can be conveniently obtained does not provide assurance that the critical expression of either a genetic or environmentally influenced process has been described. Such measurements are only the outward signs of a complex array of physiological functions and responses; they are not discrete genetic or physiological characters; they are only abstractions used to facilitate the description of certian observation^.^ Blood pressure is a reading taken with the aid of a * Osborne, R. H., F. V. De George, and J. A. L. Mathers, The Variability of Blood Pressure: Basal and Casual Measurements in Adult Twins (in preparation).

4 Osborne: The Host Factor in Disease 605 mechanical device and represents an end point of a long and complicated chain of biological processes in relation to an untold number of environmental influences. To understand the genetic and environmental forces reflected in measured levels of the blood pressure it will be necessary to define more effectively the processes this measurement purports to describe. A second and somewhat different situation is exemplified by the measured levels of the serum cholesterol. The serum cholesterol is of interest because of its probable relationship to atherosclerotic cardiovascular disease. We are all acquainted with the reports in the press and in the professional literature of the differences in prevalence of atherosclerotic disease in different areas and among different peoples : atherosclerotic changes being relatively more prevalent in advanced societies, particularly among professional and higher income groups (for example, physicians in New York City) as compared to groups with a marginal subsistence (for example, Bantu of South Africa). Parallel differences have been observed in serum cholesterol levels, which have been in turn related to differences in fat intake. Family studies have indicated that both atherosclerotic disease and excessive serum lipid levels are familial. Gedda and Poggill very recently reported twinstudy evidence on the genetic regulation of the serum cholesterol. These investigators studied 50 monozygotic and 50 dizygotic twin pairs ranging from 6 to 19 years of age. As comparisons were made on intrapair differences, environmental factors were controlled since both members of each twin pair were living in the same home with their parents at the time of study. The statistical analysis was based upon classifications of concordant and discordant pairs. Remarkable agreement was obtained for the monozygotic twin pairs: 37 pairs agreed perfectly in their cholesterol levels, whereas only 12 pairs of the dizygotic twins showed absolute agreement. This difference in concordance between monozygotic and dizygotic twin pairs is highly significant. According to Gedda and Poggi this gives evidence of the genotypic dependence for the biogenesis of the cholesterol. In an earlier study of 43 monozygotic and 39 dizygotic adult twin pairs, Osborne et d.12 obtained results that differed rather interestingly from those found by Gedda and Poggi. These adult twin pairs ranged from 18 to 55 years of age. For the purposes of the analysis twin pairs were subdivided according to sex and zygosity into two groups representing twin pairs living together and living apart prior to and at the time of study. Twin pairs were classified as living together if the two members were sharing the same home and taking at least two meals a day together. Rlonozygotic twins living together were compared to dizygotic twins living together, and monozygotic twins living apart were compared to dizygotic twins living apart. The dizygotic differences were found to be consistently larger than those of the monozygotic twins, but in no instance was the difference statistically significant; they were certainly far short of the magnitude of differences reported by Gedda and Poggi. How might we account for the contrasting results from these two studies? Possibly greater differences in the external environment between the two members of an adult twin pair, even when living together, overshadow the

5 606 Annals New York Academy of Sciences genetic control of serum lipidi3 levels to be observed in children: for example, differences in occupational stress,13 which are not equated in a common domicile. Or, possibly, there is also something more fundamental than this. Serum cholesterol levels are sex- and age-dependent; children between the ages of 6 and 19 years are undergoing rapid growth and development; and adults are undergoing not only the effects of more complex environment but also have an adult physiology. Illustrated here are: (1) the importance of the environmental factor of age with all its potential ramifications; and (2) measurements of even a relatively well-defined phenotypic character such as serum cholesterol do not necessarily represent an expression of the same biological processes when obtained under different environmental conditions. The complexity of the interrelationship of genetic and environmental forces illustrated by these examples is extremely important, but within the usual context of medical investigations I am most concerned with another fundamental aspect of this problem that is also illustrated by these data. The intrapair variances for total cholesterol, cholesterol esters, and phospholipids of the twin pairs living apart are consistently larger than for those living together in all zygosity and sex categories. When the data are arranged according to both the genetic and environmental similarity of the twin pairs, the cumulative effects of these two forces are clearly seen. In other words, monozygotic twins living together have the most similar serum lipid levels, and dizygotic twins living apart the most dissimilar; between these two extremes are to be found the monozygotic twins living apart and the dizygotic twins living together. It is apparent that variations in serum lipids result from an interplay of genetic and environmental influences; it cannot be presumed that genetic factors will be equally important in all environments, or that the environmental tolerances of one population will necessarily equal those of another population. To recognize the role of the host in the etiology of disease the nature of genet ic-environment interaction must be understood. In all probability thisapplies to the majority of diseases and to the attributes by which a disease can be defined: attributes that reflect deviations in the normal processes by which man has achieved adaptation to his varied environment. Rejerences 1. PAUL, J. R Clinical Epidemiology. Univ. Chicago Press. Chicago, Ill. 2. FINN, R Protective factors in erythroblastosis (Abstr.). Ann. Human Genet. (London). 24: vi. 3. DORZHANSKY, T Evolution, Genetics, and Man. Wiley. New York, N. Y. 4. DOBZHANSKY, T. & B. WALLACE The problem of adaptive differences in human populations. Am. J. Human Genet. 6: MATHER, K Biometrical Genetics. Dover. New York, N. Y. 6. MATHER, K Polygenic Inheritance in Clinical Genetics. A. Sorshy, Ed. Mosby. St. Louis, Mo. 7. PENROSE, L. S The Biology of Mental Defect. Sigwick & Jackson. London, England. 8. SNYDER, L. H Human heredity and its modern application. American Sci. 43: PICKERJNG, G. W High Blood Pressure. Grune & Stratton. New Tork, N. Y. 10. M~ALL, W. E. & P. D. OLDHAM Factors influencing arterial blood pressure in the general population. Clin. Sci. 17: 409.

6 Osborne: The Host Factor in Disease GEDDA, L. & D. POGGI Sulla regolazione genetica del colesterolo ematico (Uno studio su 50 coppie gemellari MZ e 50 coppie DZ). Acta Genet. Med. et Gemelel. IX: OSBORNE, R. H., D. ADLERSBERG, F. V. DE GEORGE & C. WANG Serum lipids, heredity, and environment: a study of adult twins. Am. J. Med. 26: THOMAS, C. & E. A. MURPHY Further studies on cholesterol levels in the Johns Hopkins medical students: the effect of stress at examination. J. Chronic Diseases. 8: 661.