7
Are Genetic Factors Involved in Racial and Ethnic Differences in Late-Life Health?

James V. Neel

Introduction

In the United States, when we think about racial or ethnic differences in late-life health (and the possible genetic bases for these differences), our thoughts tend to center on the comparison of blacks and whites, and because there is so much more information on these two groups than any others, this presentation concentrates on some possible differences between them. First, I briefly discuss two well-understood disease entities of early onset that are almost entirely restricted to blacks and use these diseases as a point of departure for the possible health implications of racial and ethnic differences in allele frequencies with respect to single-locus polymorphisms. (An allele is any one of two or more different genes that may occupy the same position on a specific chromosome.) I then turn to more complex situations and consider two diseases that result from an interaction between a complex genetic substrate and an equally complex environment. Both of these diseases are characterized by black-white differences in morbidity and mortality. Finally, I briefly discuss the prospects for improving our understanding of whether there really are any genetic differences between blacks and whites with respect to susceptibility to the major diseases of late (as contrasted to early) life.

At the outset, I would like to acknowledge the debt this paper owes the comprehensive treatment entitled Genetic Variation and Disorders in Peoples of African Origin by Bowman and Murray (1990). Documentation of statements not otherwise referenced will as a rule be found there. However, I of course assume full responsibility for my interpretive statements.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 210
--> 7 Are Genetic Factors Involved in Racial and Ethnic Differences in Late-Life Health? James V. Neel Introduction In the United States, when we think about racial or ethnic differences in late-life health (and the possible genetic bases for these differences), our thoughts tend to center on the comparison of blacks and whites, and because there is so much more information on these two groups than any others, this presentation concentrates on some possible differences between them. First, I briefly discuss two well-understood disease entities of early onset that are almost entirely restricted to blacks and use these diseases as a point of departure for the possible health implications of racial and ethnic differences in allele frequencies with respect to single-locus polymorphisms. (An allele is any one of two or more different genes that may occupy the same position on a specific chromosome.) I then turn to more complex situations and consider two diseases that result from an interaction between a complex genetic substrate and an equally complex environment. Both of these diseases are characterized by black-white differences in morbidity and mortality. Finally, I briefly discuss the prospects for improving our understanding of whether there really are any genetic differences between blacks and whites with respect to susceptibility to the major diseases of late (as contrasted to early) life. At the outset, I would like to acknowledge the debt this paper owes the comprehensive treatment entitled Genetic Variation and Disorders in Peoples of African Origin by Bowman and Murray (1990). Documentation of statements not otherwise referenced will as a rule be found there. However, I of course assume full responsibility for my interpretive statements.

OCR for page 210
--> Two Simple Monogenic Disorders Differing In Frequency In Blacks And Whites The two very well-known diseases of blacks that are the point of departure for this presentation are sickle cell anemia and the hemolytic anemia of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. At first blush, because these diseases typically have their onset in early life, they seem very out of place in a discussion of racial and ethnic differences in late-life diseases. However, they illustrate some of the genetic nuances that enter into a discussion of late-life disease susceptibilities. Sickle cell anemia is a severe, chronic anemia, usually terminating fatally in early life, that results from homozygosity for a nucleotide substitution at the 17th position in the first intron of the gene coding for the beta chain of hemoglobin, located on chromosome 11. In the United States, about 1.8 in 1,000 black liveborn children will develop the disease. Heterozygosity for the allele, designated as S, results in the sickle cell trait and is not associated with anemia. Eight percent to nine percent of all American blacks are trait carriers. In black Africans, the frequency of trait carriers varies: it is as high as 35 percent to 50 percent in several tribes of Uganda and Tanzania and is as low as 1 percent to 2 percent in several of the Liberian tribes, with corresponding differences in the incidence of sickle cell anemia. Serjeant's monograph (1985; see also Bowman and Murray, 1990; Honig and Adams, 1986; Livingstone, 1967, 1983) presents an excellent review of the disease and its precise distribution. As soon as the genetic basis for sickle cell anemia and the sickle cell trait became apparent (Neel, 1947, 1949; Pauling et al., 1949), geneticists confronted a great paradox. Most recessively inherited, serious, essentially lethal disorders—and technically sickle cell anemia is recessively inherited—are quite rare, with an incidence of on the order of 1 in 100,000. Examples are such diverse diseases as Werdnig-Hoffman disease, mucopolysaccharidosis IV (Morquio's syndrome), branched chain ketoaciduria (maple syrup urine disease), and mucolipidosis II (I-cell disease), diseases so uncommon that only medical specialists recognize them. Noting that the sickle cell gene originated in a tropical ecosystem in which malaria, especially Plasmodium falciparum malaria, was a major cause of morbidity and mortality, Allison (1954) suggested that the relatively high frequency of the sickle cell gene was due to the fact that the sickling phenomenon conferred protection against the disease. This followed an earlier suggestion by Haldane (1949) that another hematological disorder, thalassemia major (a severe chronic anemia usually fatal in childhood), known at that time to be relatively common in parts of Italy, owed its incidence to the fact that people heterozygous for a thalassemia gene (those with thalassemia minor) were resistant to malaria. There followed a period of intense research activity concerning the validity of the hypothesis. Three distinct lines of evidence now suggest it is correct (details in Bowman and Murray, 1990; Livingstone, 1967, 1983):

OCR for page 210
--> There is a strong positive correlation between the frequency of the hemoglobin S allele in a given geographic area and the present (or past) prevalence of infection with falciparum malaria. The morbidity and mortality associated with infections with falciparum malaria are less in persons with the sickle cell trait than in persons without the trait. Although the findings are not without controversy, a number of studies suggest that the red blood corpuscles of persons with the sickle cell trait provide a suboptimal environment for the growth of the parasite P. falciparum. Conversely, on the basis of samples collected in Africa, our group was unable to find evidence for the high mutation rate required if such a high rate was the mechanism maintaining the frequency of the hemoglobin S allele (Vanderpitte et al., 1955). Thus, in a malarial environment, heterozygosity for the hemoglobin S allele confers protection against P. falciparum, and means increased survival and reproduction of these heterozygotes. This improved survival of the heterozygote offsets the loss of hemoglobin S alleles when they are in the homozygous state. It is a successful genetic adaptation, but it carries a rather high price tag. The G-6-PD deficiency trait came to medical attention in a somewhat unusual fashion. Following World War II, there was a major effort to develop better antimalarial drugs, especially those effective against P. falciparum malaria. Much of this investigation involved synthesizing and clinically testing compounds of the 8-aminoquinoline family; the clinical investigations took place largely at the University of Chicago under the direction of A. Alving and associates. In field trials, it became apparent that two early antimalarial compounds (pamaquine and primaquine) induced a transitory hemolytic anemia in some blacks, but more rarely in whites. A long series of investigations demonstrated that the anemia was the result of an inherited defect in the gene encoding for the enzyme G-6-PD, located on the sex chromosome. With respect to G-6-PD deficiency, hemizygous males (with one X chromosome) were either positive or negative, but females could be positive/positive, positive/negative, or negative/negative. In females, only the third genotype is affected, and since this requires the presence of two defective alleles (rather than one, as in males), G-6-PD deficiency is much less common in females than in males. Extensive genetic studies that included biochemical characterization of the deficient enzyme revealed that the molecular basis of the G-6-PD deficiency was rather different from that of the sickling trait. Whereas a single very specific mutation of the beta globin locus produces the sickling trait, with respect to the G-6-PD protein, many different mutations affect the amount in which the enzyme occurs and the efficiency of its action. G-6-PD deficiency is now known to be the cause of the transient hemolytic anemia that some people experience after eating the fava bean and is sometimes associated with a congenital nonspherocytic

OCR for page 210
--> hemolytic anemia. The deficiency may precipitate anemia in some individuals with viral infections, such as viral hepatitis. In deficient individuals, in addition to the 8-aminoquinolines, an impressive list of other drugs may cause a hemolytic anemia. By now, population surveys for the frequency of the G-6-PD deficiency are almost as numerous as surveys for the frequency of the sickle cell trait. More than 300 different G-6-PD variants have been identified, and at least 100 of these are relatively common in the males of the populations in which they occur. The higher frequencies are encountered in peoples living in tropical or near-tropical environments. Thus, in addition to African blacks (in whom the frequency of deficient males may vary from zero to 32%, according to tribal affiliation), the frequency of G-6-PD deficient males is as high as 36 percent in some communities of Sephardic Jews, up to 48 percent in areas of Sardinia, 20 percent in some Iranian groups, 15 percent in the Khmer of Cambodia, and 13 percent in the Punjabis of India. The frequency in male African Americans is some 14 percent. The high frequency of G-6-PD deficient males in these various populations raises the same questions as the high frequency of the hemoglobin S allele, and a similar explanation, the relative resistance of allele carriers to malaria, has been put forth. The evidence in favor of this explanation is similar to the types of evidence adduced earlier to explain the frequency of the hemoglobin S allele, although in general not as convincing. Again, a trait, G-6-PD deficiency, that under certain conditions appears to be deleterious has been carried to a relatively high frequency because it confers a benefit in a specific situation. The frequency of the allele of the beta globin chain of hemoglobin associated with the sickling phenomenon, and the deficiency alleles of the G-6-PD locus, are examples of genetic polymorphisms. A genetic locus is said to be polymorphic if one or more variant alleles are known for that locus and at least one of the variant alleles has a frequency of 1 percent. This is an arbitrary definition—there is no magic, logical dividing line at 1 percent—but the definition is operationally useful. The genetic loci encoding for the ABO and Rh blood groups are other well-known examples of polymorphic systems. Genetic polymorphisms are in theory of three principal types. First, there are transient polymorphisms that result when an established allele is in the process of being replaced by an allele that confers a selective advantage. Second, there are genetic polymorphisms that result when a new mutation of no particular selective value by chance ''drifts" upward in its frequency, to the point where it is polymorphic. Such polymorphisms are most often encountered in small, isolated populations. Third, there are balanced polymorphisms, maintained by the operation of opposing selective forces. The sickling alleles and the G-6-PD deficiency alleles are representatives of balanced polymorphisms. Homozygosity for the hemoglobin S allele is usually inconsistent with reproduction because the homozygotes usually die in childhood. Homozygosity for a G-6-PD deficiency allele (or hemizygosity in the case of a male) by no means confers the handicap of sickle cell anemia but must still

OCR for page 210
--> be regarded as impairing the fitness of the homozygote. But in both cases, the alleles have a positive side, conferring resistance to malaria, and the frequency of the allel in a population is determined by a balance between positive and negative selective forces. What possible light do these two genetic systems throw on disease susceptibilities in late life? Very simply, in an environment where P. falciparum malaria is epidemic—and malaria is making a comeback—people with the sickle cell trait or with G-6-PD deficiency trait should at any age level enjoy superior health through a "natural" resistance to the disease. On the other hand, the drug sensitivities of the male with the G-6-PD deficiency persist throughout life and may first become manifest with the increased medication of senior citizens. But these two diseases illustrate an additional point: as the environment alters, a genetic trait that once conferred a selective advantage may lose its advantage. For the record, I should make it clear that the possession of certain unusual alleles in relatively high frequency is by no means unique to blacks. I think of the Tay-Sachs alleles in Ashkenazic Jews, cystic fibrosis alleles in white populations of North European extraction, and beta-thalassemia alleles in whites of the eastern Mediterranean basin. The beta-thalassemia alleles in heterozygotes probably confer protection against P. falciparum malaria, but the reason for the relatively high frequency of the other two sets of alleles is unknown. Differences In Allele Frequency For Genetic Polymorphisms In Blacks And Whites Not until genetics took on strong biochemical overtones, in the 1950s and 1960s, was it appreciated how common genetic polymorphisms were. The technique of electrophoresis, combined with enzyme activity stains, revealed that roughly half the proteins studied could have genetic polymorphisms. With the advent of DNA genetics in the 1970s and 1980s, especially the use of so-called restriction site enzymes to define restriction fragment length polymorphisms (the now well-known RFLPs), it became apparent that polymorphisms were very common at the DNA level; we have recently estimated that humans are polymorphic at something like 3 × 106 nucleotide sites (Bittles and Neel, 1994). Geneticists have been overtaken by an avalanche of genetic variations, and defining their functional significance is a core problem of contemporary population genetics. How much of this variation is flotsam and jetsam, noise in an imperfect genetic system (i.e., neutral polymorphisms), and how much is of biological significance, representing balanced polymorphisms such as the sickle cell and G-6-PD systems, or polymorphisms in which one allele is in the course of being substituted for another through biological selection? On theoretical grounds (Kimura, 1983) and from the results of studies on the outcome of consanguineous marriages (Bittles and Neel, 1994; Neel, 1993), we can argue that much of this variation has no effect on survival and reproduction, but the ex-

OCR for page 210
--> amples of the sickle cell trait and G-6-PD deficiency—not to mention evolutionary theory—force us to assume that some of the variation has functional significane that we must strive to understand. Most of the readers of this paper will be surprised to learn how poorly sorted out the polymorphisms are in this regard. Perhaps the best current example of human polymorphic loci associated with disease susceptibilities is the major histocompatibility complex, a set of genetic loci that are responsible for the near immunological uniqueness of each human being (except identical twins). The best known of the loci in this complex code for the human leukocyte antigens are termed HLA loci; the four best defined of the loci are designated HLA-A, HLA-B, HLA-C, and HLA-D, with HLA-D a series of sub-loci. Each of these loci is highly polymorphic; at last count, the number of established alleles at each locus varied from 18 to 60 for the A, B, and C loci and from 4 to 58 for the 6 D sub-loci, and the number is still growing. The various possible combinations of these alleles in each individual (plus other inherited antigenic differences not discussed in this paper) create an almost astronomical number of immunological genotypes and phenotypes (references in Ayala et al., 1994; see also Tsugi et al., 1992). It is now well established that certain HLA alleles confer susceptibility to specific diseases of middle or late life. Many of these diseases are autoimmune disorders, so called because they appear to occur when a person's immune system elaborates specific antibodies that react with that person's own tissues. The precise basis for these disease associations remains under active debate: Is it the specific HLA allele that confers the susceptibility or a gene closely linked to the HLA allele? In fact, the associations undoubtedly result from a mixture of both mechanisms. Be this as it may, some of the more striking disease associations established in whites are shown in Table 7-1. It is noteworthy that blacks are not represented in these studies. It is not clear whether the diseases in question are much less common in blacks than in whites or whether the necessary studies simply have not been carried out. Note that there are significant and even striking differences between blacks and whites in the frequency of some of the alleles of the HLA system, including alleles A2, A3, and B27, which are associated with several diseases in whites, as Table 7-2 shows (see also Tsugi et al., 1992). Most of these HLA-associated diseases are rare, but collectively, they represent a considerable medical burden. Of special interest in the present context is the recently demonstrated protection against P. falciparum malaria in West Africans conferred by an HLA-B-group haplotype, HLA-Bw53, and a D-group haplotype, DRB1*1302-DQB1*0501 (Hill et al., 1991, 1992). These haplotypes, relatively common in West Africa, are rare in other racial groups. The protection to the individual is not as great as that conferred by heterozygosity for the sickle cell allele, but since these alleles have a higher frequency in West Africa than the sickle cell allele, the protection to the population as a whole appears to be somewhat greater than that afforded by hemoglobin S heterozygosity. Here would seem to be a clear ex-

OCR for page 210
--> TABLE 7-1 Some Associations Between HLA Type and Specific Diseases       Antigen Frequency       Disease Group HLA type Patients Control Subjects Relative riska P value Number of Studiesb Joint Disease Ankylosing spondylitis White B27 89.8 8.0 87.8 1.0 × 10-10 17   Japanese B27 66.7 0.0 305.7 1.0 × 10-10 1   Haida Indians B27 100.0 50 34.4 1.7 × 10-9 1   Bella Coola Indians B27 100.0 20.2 20.2 1.9 × 10-2 1   Pima Indians B27 36.0 18.0 2.6 1.0 × 10-3 1 Reiter's disease White B27 78.2 8.4 35.9 1.0 × 10-10 8 Yersinia arthritis White B27 79.4 9.4 24.3 1.0 × 10-10 2 Salmonella arthritis White B27 66.7 8.6 17.6 3.6 × 10-10 2 Psoriatic arthritis White B13 19.8 5.5 4.8 9.6 × 10-10 5 Central joints   B27 40.2 8.7 8.6 1.0 × 10-4 5     Bw17 11.6 5.5 2.5 4.6 × 10-3 5     Bw38 22.7 2.9 9.1 5.6 × 10-6 5 Peripheral joints White B13 9.9 5.5 2.3 9.5 × 10-3 5     B27 15.5 8.7 2.5 3.5 × 10-4 5     Bw17 24.8 5.5 5.8 1.0 × 10-10 5     Bw38 12.6 2.9 4.5 3.2 × 10-4 5 Juvenile rheumatoid arthritis White B27 26.4 8.5 4.7 1.0 × 10-10 7 Rheumatoid arthritis White Dw4 42.2 15.7 3.0 1.0 × 10-5 2   White Cw3 30.0 17.0 2.7 1.0 × 10-2 1

OCR for page 210
--> Disease of the Endocrine Glands Thyroid disease Graves' disease White B8 36.7 21.7 2.13 1.0 × 10-6 6     Dw3 50.0 21.7 4.0 1.0 × 10-4 3   Japanese Bw35 56.8 20.5 4.97 1.0 × 10-5 1 deQuervain's thyroiditis White Bw35 76.9 12.5 22.2 1.0 × 10-10 2 Adrenal disease Addison's disease White B8 50.0 22.7 3.9 7.3 × 10-6 2     Dw3 70.0 21.7 10.5 1.0 × 10-3 1 Pancreatic disease Diabetes White B8 36.7 21.8 2.1 1.0 × 10-10 8 Juvenile onset diabetes   Bw15 22.8 14.9 2.1 1.0 × 10-10 8 Gastrointestinal Tract Disease Chronic active White A1 41.6 28.4 1.8 6.4 × 10-5 5 hepatitis   B8 44.2 20.3 3.0 1.0 × 10-10 5     Dw3 60.0 21.7 7.2 1.0 × 10-3 2 Celiac disease White A1 63.7 29.5 4.2 1.0 × 10-10 7 (gluten enteropathy)   B8 71.2 23.1 8.8 1.0 × 10-10 9     Dw3 98.0 15.0 278 1.0 × 10-5 1 Hemochromatosis White A3 78.4 27.0 9.5 2.1 × 10-11 2     B14 25.5 3.4 9.23 5.3 × 10-5 1 Ulcerative colitis Japanese B5 80.0 30.8 9.3 1.0 × 10-3 1 Pernicious anemia White B7 35.8 22.1 2.2 1.2 × 10-4 3

OCR for page 210
-->       Antigen Frequency       Disease Group HLA type Patients Control Subjects Relative riska P value Number of Studiesb Skin Disease Psoriasis White B13 19.7 4.5 4.65 1.0 × 10-10 6     Bw17 26.2 7.8 4.7 1.0 × 10-10 6     Bw37 7.7 1.4 5.4 1.0 × 10-10 3 Dermatitis herpetiformis White A1 69.0 30.1 4.4 1.0 × 10-10 5     B8 77.0 24.7 9.2 1.0 × 10-10 6 Pemphigus vulgaris White A10 39.3 12.7 3.1 1.2 × 10-4 3 Herpes labialis White A1 55.6 25.1 3.7 1.3 × 10-6 1     B8 33.3 16.8 2.5 3.5 × 10-4 1 Eye Disease Anterior uveitis White B27 56.8 7.7 15.4 1.0 × 10-4 2 Vogt-Koyanagi-Harada disease Japanese B22J 42.9 13.2 4.5 2.0 × 10-2 1 Malignant Disease Hodgkin's disease White A1 31.1 39 1.4 1.0 × 10-6 17     B5 10.6 16 1.6 1.0 × 10-6 17     B8 23.7 29 1.3 1.0 × 10-4 17     Bw18 7.1 13 1.9 1.0 × 10-6 17 Acute lymphatic leukemia White A2 60.0 53.6 1.3 1.0 × 10-2 10     B8 29.0 23.7 1.3 1.0 × 10-2 10     Bw18 29.0 25.2 1.3 1.0 × 10-2 10 Nasopharyngeal cancer Chinese Sia2 44.0 21.0 1.9 1.0 × 10-3 1 a The relative risk is the ratio of the proportion of diseased individuals among carriers of a specific genetic trait to the proportion of diseased individuals among people who do not carry that trait. b The relative risk figures are derived from the combined data set. SOURCE: Adapted from Vogel and Motulsky, 1979.

OCR for page 210
--> TABLE 7-2 A Comparison of Three Ethnic Groups with Respect to the Frequency of Certain HLA Types   HLA-A Frequency     HLA-B Frequency   Gene Locus European Whites (n = 228) African Blacks (n = 102) Japanese (n = 195) Gene Locus European Whites (n = 228) African Blacks (n = 102) Japanese (n = 195) A1 0.16 0.04 0.01 B5 0.06 0.03 0.21 A2 0.27 0.09 0.25 B7 0.10 0.07 0.07 A3 0.13 0.06 0.007 B8 0.09 0.07 0.002 A23 0.02 0.11 — B12 0.17 0.13 0.07 A24 0.09 0.02 0.37 B13 0.03 0.02 0.008 A25 0.02 0.04 — B14 0.02 0.04 0.005 A26 0.04 0.05 0.13 B18 0.06 0.02 — A11 0.05 — 0.07 B27 0.05 — 0.003 A28 0.04 0.09 — B15 0.05 0.03 0.09 Aw29 0.06 0.06 0.002 Bw38 0.02 — 0.02 Aw30 0.04 0.22 0.005 Bw39 0.04 0.02 0.05 Aw31 0.02 0.04 0.87 B17 0.06 0.16 0.006 Aw32 0.03 0.02 0.005 Bw21 0.02 0.02 0.02 Aw33 0.007 0.01 0.02 Bw22 0.04 — 0.07 Aw43 — 0.04 — Bw35 0.10 0.07 0.09 Blank 0.02 0.11 0.04 B37 0.01 — 0.008         B40 0.08 0.02 0.22         Bw41 — 0.02 —         Bw42 — 0.12 —         Blank 0.04 0.18 0.08   HLA-C Frequency     HLA-DR Frequency   Gene Locus European Whites (n = 321) African Blacks (n = 101) Japanese (n = 203) Gene Locus European Whites (n = 334) African Blacks (n = 77) Japanese (n = 164) Cw1 0.05 — 0.11 DRw1 0.06 — 0.05 Cw2 0.05 0.11 0.01 DRw2 0.11 0.09 0.17 Cw3 0.09 0.06 0.16 DRw3 0.09 0.12 — Cw4 0.13 0.14 0.04 DRw4 0.08 0.04 0.14 Cw5 0.08 0.01 0.01 DRw5 0.15 0.07 0.05 Cw6 0.13 0.18 0.02 DRw6 0.09 0.10 0.07 Blank 0.47 0.50 0.53 DRw7 0.16 0.07 —         W1A8 0.06 0.07 0.07         Blank 0.21 0.45 0.45   SOURCE: Bowman and Murray, 1990: Table 5.3. Original data from Conference Workshop on Histocompatibility Testing (1978: Table 6.1-6.4). Reprinted by permission of Munksgaard International Publishers.

OCR for page 210
--> ample of an ethnic difference in susceptibility to a disease as great as the sickle cell example. Other possible genetic protective mechanisms against malaria in blacks have been recently reviewed by Miller (1994, 1995). It is clear that in meeting the serious challenge to survival that malaria poses, the process of natural selection has drawn on multiple, diverse genetic mechanisms to blunt the effects of the disease. A possible polymorphism-disease association of whites that is currently receiving a great deal of attention is the highly significant correlation between Alzheimer's disease and possession of the 4 allele of the apolipoprotein E (Apo E) system (Chartier-Harlin et al., 1994; Corder et al., 1993; Noguchi et al., 1993; Payami et al., 1993; Poirier et al., 1993; Saunders et al., 1993; Strittmatter et al., 1993). Eight abstracts from the fall 1994 meeting of the American Society of Human Genetics confirmed this association (Crawford et al., 1994; Houlden and Rossor, 1994; Jarvik et al., 1994; Kamboh et al., 1994; Martinez et al., 1994; Okuizumi et al., 1994; Poduslo and Schwankhaus, 1994; Sahota et al., 1994). For whites, this is now one of the most firmly established marker-disease associations in genetic medicine. Linkage studies have already suggested that there are at least three genetic loci where the presence of an abnormal allele may result in a condition that meets the criteria of Alzheimer's disease (e.g., Corder et al., 1993; Goldin and Gershon, 1993; Pericak-Vance et al., 1993); heterogeneity is also suggested by segregation analysis (Rao et al., 1994). It will be very important to determine whether the three types of Alzheimer's disease that these loci define all exhibit the Apo E 4 association. If the association is with only one of these three loci, then the high statistical correlation that has been observed would require a very strong association with that one locus. The 4 allele occurs about twice as frequently in U.S. blacks (0.26) as in U.S. whites (0.13) (summary in Gerdes et al., 1992). The data on black-white differences in the frequency of Alzheimer's disease are scanty but favor a lower incidence of Alzheimer's in blacks (de al Monte et al., 1989; Molgaard et al., 1990; Schoenberg et al., 1985). The limited data on an Apo E 4 allele association with Alzheimer's in blacks are contradictory; Mayeux et al. (1993) find no relationship but Sahota et al. (1994) find a strong association. Further studies on this association will be as important as further studies on the associations of HLA alleles with disease in blacks, since cross-racial studies of both of these disease associations will reveal much about the specificity of the association. Most of the human genetic polymorphisms have been discovered in white populations, and studies of the comparative frequency of the variant alleles in whites and blacks are often limited. However, in a majority of instances where proper population surveys have been done, there are statistically significant differences between the allele frequencies of the polymorphisms in the two racial groups. In some instances, these differences are very striking. For instance, the frequency of the Ro (cDe) allele of the Rh system, associated with Rh hemolytic disease, is relatively very high in black Africans and African Americans (0.50 to

OCR for page 210
--> 140/90). The justification is the belief that when these or higher levels are sustained over a prolonged period of time, there are departures from health, however that be defined. Likewise, the definition of diabetes mellitus is reached when the fasting plasma glucose exceeds 140 mg/dl or when the plasma glucose exceeds 200 mg/dl 2 hours after the ingestion of a standard (75 grams) load of glucose. Again, this is based on the belief that at this level of impairment of glucose metabolism, there are departures from health. It is customary to distinguish between two principal types of diabetes: (1) diabetes of relatively early life and sudden onset, in the medical management of which insulin is necessary from the outset, and (2) diabetes of relatively late life and gradual onset, in the medical management of which insulin is not necessary until late in the disease if at all. The former is termed insulin-dependent diabetes mellitus, the latter non-insulin-dependent diabetes mellitus. In this brief presentation, we consider only the second type of diabetes. That there are differences between blacks and whites in the frequency and severity of these two diseases is well established (Anderson and McManus, 1996; see also Roseman, 1985). However, there are some tricky aspects to these racial comparisons. The National Health and Nutrition Examination Survey (NHANES) of 1979-1982 revealed that for all ages, the rate of diagnosed diabetes per 1,000 people was 32 for blacks and 24 for whites. The vast majority of these diagnoses were of non-insulin-dependent diabetes mellitus (insulin-dependent diabetes mellitus seems less common in blacks). However, I remind you that the inability to metabolize glucose is a continuously distributed trait. The NHANES during 1979-1981 administered oral glucose tolerance tests to a large sample of blacks and whites in whom diabetes had not been diagnosed. For all ages (20 to 74 years) and both sexes, the prevalence of undiagnosed diabetes mellitus was 80/1,000 in whites and 123/1,000 in blacks, but the prevalence of impaired glucose tolerance (which may be regarded as a way station to non-insulin-dependent diabetes mellitus) was 95/1,000 in whites and 34/1,000 in blacks. For all three categories combined—the diagnosed, those with undiagnosed diabetes, and those with impaired glucose tolerance—the prevalence was 189/1,000 in blacks and 199/1,000 in whites. One could argue from this finding that the magnitude of the predisposed group was about the same in blacks and in whites but that a larger fraction of blacks have realized that predisposition, as the disease is now defined. The second salient point about these two diseases is that they are of very gradual onset. In the children of parents with non-insulin-dependent diabetes mellitus, there are statistically significant departures from normal glucose metabolism in the third decade, even though the degree of impairment that justifies the (arbitrary) diagnosis of non-insulin-dependent diabetes mellitus is not usually reached until the fifth or sixth decade (cf. Neel et al., 1965). Likewise, in retrospect, individuals with borderline hypertension (average age 31.4 years) exhibited, in comparison with control subjects, small but significant elevations during childhood and immediately after puberty (Julius et al., 1990).

OCR for page 210
--> The argument over the degree to which these ethnic differences in non-insulin-dependent diabetes are environmentally triggered versus the degree to which they are based on specific genes that differ in frequency in the two ethnic groups—like the polymorphisms previously discussed—goes back to the recognition of the racial and ethnic differences. Since there is no agreement as to the basic defect or defects in either of the two diseases, the argument has been relatively uninhibited by troublesome facts. One salient point is clear: both of these diseases are diseases of modern civilization, however civilization be defined. Hypertension is very uncommon in tribal populations adhering to traditional lifestyles (reviewed in Page, 1978). For instance, we encountered no hypertensives in quite unacculturated Xavante and Yanomama Amerindians (Neel et al., 1964; Oliver et al., 1975). Numerous studies on native Africans document the increase in blood pressure that occurs with the transition from a relatively unacculturated rural setting to urban life, with hypertension then apparently as prevalent as in U.S. blacks (reviewed in Kaufman and Barkey, 1993; see especially Scotch, 1963). The ''triggers" that have been invoked to explain this increase range from a greater salt intake to a complex of socioeconomic factors that create stress. Since tribal life is by no means without its stresses, one must be careful not to use the term stress loosely. Non-insulin-dependent diabetes mellitus is likewise less prevalent in rural African blacks than in urban African blacks, but in both groups it is well below the prevalence in U.S. blacks (reviewed in Roseman, 1985). With reference to the genetics of hypertension, numerous studies have established its familial nature (reviewed in Burke and Motulsky, 1990; Ward, 1990). Although most of these studies involve whites, the disease is no less familial in blacks (Rotini et al., 1994). However, the correlation between adult siblings usually varies from 0.2 to 0.3 for both systolic and diastolic pressures, and for parents and offspring, the variation is the same or somewhat lower (reviewed in Burke and Motulsky, 1990). For monozygous twins, the correlations were 0.55 for systolic pressure and 0.58 for diastolic, whereas for dizygous twins, the corresponding figures were 0.25 and 0.27. These are, of course, significant but well below those expected of a continuously distributed trait that is completely determined genetically. Thus, while these data certainly establish the familial nature of hypertension, I have to remind you of the old truism that all that is familial is not genetic, a stricture especially appropriate for a disease such as hypertension (cf. especially Cooper and Rotini, 1994). With reference to the genetics of non-insulin-dependent diabetes mellitus, the disease has long been recognized as strongly familial, and various modes of inheritance have been suggested. Many of the problems recognized 30 years ago in attempts to elucidate its genetic basis (reviewed in Neel, 1962; Neel et al., 1965) persist today (Leslie, 1993). In one representative study, the risks for siblings and children of a person with the disease were placed at 38 percent and 33 percent, respectively (Köbberling and Tillil, 1982), and these are minimal

OCR for page 210
--> estimates because additional cases will develop subsequent to the study. Concordance in monozygotic twins, given the detection of the disease in a parent or sibling, is greater than 90 percent (Barnett et al., 1981). Although in several studies only about 10 percent to 30 percent of the children of two diabetic parents were similarly affected (Ganda and Soeldner, 1977; Tattersall and Fajans, 1975), correction for the age of onset brought the anticipated proportion of those affected to 90 percent to 100 percent. Again, one must remember that all that is familial does not necessarily have a genetic basis in the sense of segregating, identifiable alleles. Although essential hypertension and non-insulin-dependent diabetes mellitus are diseases of later life, they may develop during reproductive life and impose a reproductive handicap in their various manifestations. The genes for susceptibility appear to be relatively common and widespread. This pattern raises the same question as was raised by the frequency of the sickle cell trait. Some years ago, I raised the possibility that what we now regard as genes for susceptibility to diabetes mellitus served a useful function prior to civilization but did not become fixed because they were balanced by opposing selective forces. I referred to the diabetic predisposition as a "thrifty genotype," which contributed to our metabolic efficiency in lean times (Neel, 1962, 1976, 1982). Others have pursued a similar hypothesis regarding the predisposition to hypertension (Julius and Jamerson, 1994). As we come to better understand the molecular genetics for these predispositions, it will be of interest to see how this hypothesis plays out. Investigators accept that diseases as varied in age of onset and course as non-insulin-dependent diabetes mellitus and essential hypertension are genetically heterogeneous. A number of rare subtypes of each, often associated with syndromes, are known, and these are excluded from this general discussion. But the remaining cases are almost surely genetically heterogeneous, and efforts to tease out subtypes continue. The most notable success in recognizing a subtype of non-insulin-dependent diabetes mellitus involves the relatively uncommon maturity onset diabetes of youth, in which impairment of sugar metabolism has an early onset, progresses slowly, and appears to be inherited as a simple dominant trait (Tattersall, 1974). In the 20 years since its recognition, the maturity onset diabetes of youth has been divided into three subtypes, one tightly linked to the genetic markers ADA and D20S16 on chromosome 20q, one due to abnormalities in the glucokinase gene on chromosome 7p, and one with neither of these genetic linkages (reviewed in Fajans et al., 1994). Likewise, there are rare, simply inherited types of hypertension (reviewed in Williams et al., 1994). For example, a rare type of hypertension identified some 20 years ago (New and Peterson, 1967; Sutherland et al., 1966) has been shown to be due to a chimeric 11 beta-hydroxylase/aldosterone synthetase gene located on chromosome 8q (Lifton et al., 1992). Further rare genetic subtypes of both diseases will undoubtedly be defined, but the body of both diseases will remain complexly multifactorial.

OCR for page 210
--> Both non-insulin-dependent diabetes mellitus and essential hypertension are often encountered in obese individuals. Since obesity is also accompanied by a decreased life expectancy, it may be defined as a disease, and it too is a disease rare in tribal peoples. As in the case of non-insulin-dependent diabetes mellitus and essential hypertension, the race to identify "obesity susceptibility" genes is on. Because all three of these diseases are relatively common, they might be expected occasionally to occur together by chance. In fact, the frequency of the congruence of truncal/abdominal (android) obesity with non-insulin-dependent diabetes mellitus and hypertension in the same person far exceeds the expectation based on chance (cf. Carmelli et al., 1994; Rice et al., 1994; Sims and Berchtold, 1982). It is increasingly necessary to see these three conditions as a disease complex (e.g., Björntorp, 1992; Landsberg, 1986; Reaven, 1988; Rice et al., 1994) that has emerged with the profound changes in lifestyle that accompany modern civilization, and the genetic studies of the future must deal with this complex, which amounts to the thrifty genotype updated. As we all know, the disease manifestations of non-insulin-dependent diabetes mellitus and essential hypertension are numerous and varied. These manifestations appear to differ in blacks and whites. For instance, it appears that blacks with non-insulin-dependent diabetes mellitus may have a relatively higher frequency of microvascular disease, retinopathy, renal disease, and peripheral vascular disease than whites (Cowie et al., 1989; Harris et al., 1994; Roseman, 1985). Adjusting these findings for the differences in the duration and severity of the disease in the two groups is difficult; it is not clear whether these differences result from specific organ susceptibilities in blacks or an earlier onset of the disease. Likewise, for hypertension, blacks have a lower risk for coronary artery disease but a higher risk for stroke and renal failures (cf. Burke and Motulsky, 1990). The data on ethnic differences in end-stage renal disease from the U.S. Renal Data System are especially striking, the incidence of blacks with end-stage renal disease averaging three to four times higher than for whites, at all age groups (Lopes et al., 1993, 1994). While the Renal Data System does not include all persons with end-stage renal disease in the United States, underreporting is more probable for blacks than for whites. Again, the question arises as to whether this reflects a greater duration of the disease in blacks. Prospects For A Better Understanding Of The Basis For Differences In Late-Life Diseases What should by now be clear is that except for a relatively few simply inherited diseases or disease-associated traits, knowledge about the possible genetic basis for the different patterns of adult onset and late-life diseases in blacks and whites is still meager. I close with a brief comment on the prospects for improving this situation. First, however, a comment on maintaining perspective is in order. Some years

OCR for page 210
--> ago (Neel, 1981), I pointed out that on the basis of 11 proteins that had been sequenced in humans (presumably from whites) and the chimpanzee, the deduced number of nucleotide substitutions distinguishing the two species was only 6 in the 4,326 nucleotides of the exons coding for these proteins in the two species. There is a 99.85 percent similarity. Now, with the use of genetic-distance techniques, the genetic distance between the major human racial and ethnic groups, based on the "standard" allele for the genes used in the study, can be shown to be only 1/25 to 1/60 of that between the human and the chimpanzee (King and Wilson, 1975). Blacks and whites then are genetically very similar indeed, leading to the expectation of resemblance, not differences, in the great majority of their genetic responses in disease-producing situations. Most of the major diseases differing in frequency between whites and blacks appear to be diseases of complex etiology, with a multifactorial genetic basis and a strong environmental component in the determination of how this inherited susceptibility is expressed. It is quite likely that there are various allele combinations that create the susceptibility and various environments that facilitate the expression of this genetic susceptibility. The varying patterns of interaction between the gene products and the milieu in which these products function create a complex epigenetic nexus that is difficult to penetrate, especially since the interactions between the components of the epigenetic nexus may be nonlinear. (I use the term epigenetic as synonymous with the complex of interactions that may intervene between gene products and their ultimate phenotypic expression.) My personal bias is that at present this epigenetic nexus differs so much between blacks and whites that it is difficult if not impossible to reach any but the simplest inferences concerning racial differences in susceptibility to complex diseases. I find myself in full accord with the pungent documentation of this viewpoint developed by Cooper and Rotini (1994), with particular reference to hypertension. Although the application of the techniques of molecular biology to genetic studies of non-insulin-dependent diabetes mellitus and essential hypertension will undoubtedly result in significant insights into the genetic component of these two diseases over the next several decades, I suspect that really definitive insights into the differences between blacks and whites that I have discussed must await progress in equalizing the epigenetic factors at work on white and black genotypes, or research designs that take advantage of unusual social circumstances. The usual research designs for epidemiological studies of traits with a strong environmental overlay—paired control subjects matched as closely as possible socioeconomically to the case subjects—do not work well in genetic studies of complex diseases because whereas it is difficult enough to match individuals, it is much more difficult to match families. Yes, there are genetic differences between blacks and whites; yes, there are clear differences in the frequency of some of the severe genetic diseases of childhood. But with reference to the diseases that are the purview of this volume, we still know very little about innate genetic

OCR for page 210
--> differences in susceptibility, and the prospects for definitive studies are dim until ways are found to deal more adequately with the epigenetic factors influencing interracial and interethnic studies. References Allison, A.C. 1954 Protection afforded by sickle-cell trait against subtertian malarial infection. British Medical Journal 1:290-294. Anderson, N.B., and C. McManus 1996 Hypertension in Blacks Across the Life Course: A Biopsychosocial Analysis. New York: Springer. Ayala, F.J., A. Escalante, C. O'Huigin, and J. Klein 1994 Molecular genetics of speciation and human origins. Proceedings of the National Academy of Sciences of the United States of America 91:6787-6794. Barnett, A.H., C. Eff, R.D.G. Leslie, and D.A. Pyke 1981 Diabetes in identical twins: A study of 200 pairs. Diabetologia 20:87-93. Bittles, A.H., and J.V. Neel 1994 The costs of human inbreeding and their implications for variation at the DNA level. Nature Genetics 8:117-121. Björntorp, P. 1992 Abdominal obesity and the metabolic syndrome. Annals of Medicine 24:465-468. Bowman, J.E., and R.F. Murray 1990 Genetic Variation and Disorders in Peoples of African Origin. Baltimore, MD: Johns Hopkins University Press. Burke, W., and A.G. Motulsky 1990 Hypertension. Pp. 170-191 in The Genetic Basis of Common Diseases , R.A. King, J.I. Rotter, and A.G. Motulsky, eds. New York: Oxford University Press. Carmelli, D., L.R. Cardon, and R. Fabsitz 1994 Clustering of hypertension, diabetes, and obesity in adult male twins: Same genes or same environment? American Journal of Human Genetics 55:566-573. Chartier-Harlin, M.C., M. Parfitt, S. Legrain, J. Perez-Tur, T. Brousseau, A. Evans, C. Berr, O. Vidal, P. Roques, V. Gourlet, J. Fruchart, A. Delacourte, M. Rossor, and P. Amouyel 1994 Apolipoprotein E, 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: Analysis of the 19q13.2 chromosomal region. Human Molecular Genetics 3:569-574. Cooper, R., and C. Rotini 1994 Hypertension in populations of West African origin: Is there a genetic predisposition? Journal of Hypertension 12:215-227. Corder, E.H., A.M. Saunders, W.J. Strittmatter, D.E. Schmechel, P.C. Gaskell, G.W. Small, A.D. Roses, J.L. Haines, and M.A. Pericak-Vance 1993 Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-923. Cowie, C.C., F.K. Port, R.A. Wolfe, P.J. Savage, P.P. Moll, and V.M. Hawthorne 1989 Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes. New England Journal of Medicine 321:1074-1079. Crawford, F., C. Bennett, A. Osborne, P. Diaz, J. Hoyne, R. Lopez, P. Roques, R. Duara, M. Rossor, and M. Mullan 1994 The APOE locus advances disease progression in late onset familial Alzheimer's disease but is not causative. American Journal of Human Genetics 55(suppl.):149(abstract).

OCR for page 210
--> de la Monte, S.M., G.M. Hutchins, and G.W. Moore 1989 Racial differences in the etiology of dementia and frequencyof Alzheimer lesions in the brain . Journal of the National Medical Association 81:644-652. Fajans, S.S., G.I. Bell, D.W. Bowden, J.B. Halter, and K.S. Polonsky 1994 Maturity-onset diabetes of the young. Life Sciences 55:413-422. Ganda, O.P., and S.S. Soeldner 1977 Genetic, acquired, and related factors in the etiology of diabetes mellitus. Archives of Internal Medicine 137:461-469. Gerdes, L.U., I.C. Klausen, I. Sihm, and O. Faergeman 1992 Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genetic Epidemiology 9:155-167. Goldin, L.R., and E.S. Gershon 1993 Linkage of Alzheimer's disease to chromosome 21 and chromosome 19 markers: Effect of age of onset assumptions. Genetic Epidemiology 10:449-454. Haldane, J.B.S. 1949 Disease and evolution. La Ricerca Scientifica Supplementa 19:68-76. Harris, E.L., M. Sheldon-Rubio, C.R. Robinson, S. Sherman, and A. Georgopoulos 1994 Racial differences in risk of developing retinopathy among persons with non-insulin-dependent diabetes (NIDDM). American Journal of Human Genetics 55(suppl.):153(abstract). Hill, A.V.S., C.E.M. Allsopp, D. Kwiatkowski, N.M. Anstey, P. Twumasi, P.A. Rowe, S. Bennett, D. Brewster, A.J. McMichael, and B.M. Greenwood 1991 Common West African HLA antigens are associated with protection from severe malaria. Nature 352:595-600. Hill, A.V.S., J. Elvin, A.C. Willis, M. Aidoo, C.E.M. Allsopp, F.M. Gotch, X.M. Gao, M. Takiguchi, B.M. Greenwood, A.R.M. Townsend, A.J. McMichael, and H.C. Whittle 1992 Molecular analysis of the association of HLA-B53 and resistance to severe malaria. Nature 360:434-439. Honig, G.R., and J.G. Adams 1986 Human Hemoglobin Genetics. New York: Springer Verlag. Houlden, H., and M. Rossor 1994 Clustering and age of onset in familial late onset Alzheimer's disease are determined at the apolipoprotein E locus. American Journal of Human Genetics 55(suppl.):152(abstract). Jarvik, G.P., W.A. Kukull, K. Goddard, G.D. Schellenberg, E.B. Laron, and E.M. Wijsman 1994 Family history and apo E genotype interaction in Alzheimer disease (AD). American Journal of Human Genetics 55(suppl.):152(abstract). Julius, S., and K. Jamerson 1994 Sympathetics, insulin resistance and coronary risk in hypertension: The "chicken-and-egg" question. Journal of Hypertension 12:495-502. Julius, S., K. Jamerson, A. Mejia, L. Krause, N. Schork, and K. Jones 1990 The association of borderline hypertension with target organ changes and higher coronary risk. Journal of the American Medical Association 264:354-358. Kamboh, M.I., S.T. DeKosky, and R.E. Ferrell 1994 Over-representation of the APOE*4 allele in autopsy confirmed early- and late-onset sporadic Alzheimer's disease. American Journal of Human Genetics 55(Suppl.):152(abstract). Kaufman, J., and N. Barkey 1993 Hypertension in Africa: An overview of prevalence rates andcausal risk factors . Ethnicity and Disease 3(suppl.):83-101. Kimura, M. 1983 The Neutral Theory of Molecular Evolution. Cambridge, England: Cambridge University Press.

OCR for page 210
--> King, M.-C., and A.C. Wilson 1975 Evolution at two levels in humans and chimpanzees. Science 188:107-116. Köbberling, J., and H. Tillil 1982 Empirical risk figures for first degree relatives of non-insulin dependent diabetics. Pp. 201-209 in The Genetics of Diabetes Mellitus, J. Köbberling and R. Tattersall, eds. London, England: Academic Press. Landsberg, L. 1986 Diet, obesity, and hypertension: An hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis. Quarterly Journal of Medicine 61:1081-1090. Leslie, R.D.G. 1993 Causes of Diabetes: Genetic and Environmental Factors. Chichester, England: John Wiley and Sons. Lifton, R.P., R.G. Dluhy, M. Powers, G.M. Rich, C. Cook, S. Ulick, and J.M. Lalouel 1992 A chimeric 11-hydroxylase/aldosterone synthetase gene causesglucocorticoid-remedial aldosteronism and human hypertension . Nature 355:262-265. Livingstone, F.B. 1967 Abnormal Hemoglobins in Human Populations: A Summary and Interpretation. Chicago: Aldine. 1983 The malaria hypothesis. Pp. 15-44 in Distribution and Evolution of Hemoglobin and Globin Loci, J.E. Bowman, ed. New York: Elsevier. Lopes, A.A.S., K. Hornbuckle, S.A. James, and F.K. Port 1994 The joint effects of race and age on the risk of end-stage renal disease attributed to hypertension. American Journal of Kidney Diseases 24:554-560. Lopes, A.A.S., F.K. Port, S.A. James, and L. Agodoa 1993 The excess risk of treated end-stage renal disease in blacks in the United States. Journal of the American Society of Nephrology 3:1961-1971. Martinez, M., J. Perez-Tur, C. Campion, F. Clerget-Darpoux, M.C. Chartier-Harlin, and the French Alzheimer Collaborative Group 1994 Increase of the Apo E4 allele frequency in a subgroup of early-onset Alzheimer's patients. American Journal of Human Genetics 55(suppl.):157(abstract). Mayeux, R., Y. Stern, R. Ottman, T.K. Tattemichi, M.-X. Tang, G. Maestre, C. Ngai, B. Tycko, and H. Ginsberg 1993 The apolipoprotein 4 allele in patients with Alzheimer's disease. Annals of Neurology 34:752-754. Miller, L.H. 1994 Impact of malaria on genetic polymorphism and genetic diseases in Africans and African Americans. Proceedings of the National Academy of Sciences of the United States of America 91:2415-2419. 1995 Impact of malaria on genetic polymorphism and genetic diseases in Africans and African Americans. Pp. 99-111 in Infectious Diseases in an Age of Change, B. Roizman, ed. Washington, DC: National Academy Press. Miller, L.H., S.J. Mason, D.F. Clyde, and M.H. McGinniss 1976 The resistance factor to Plasmodium vivax in blacks: The Duffy-blood-group genotype, FyFy. New England Journal of Medicine 295:302-304. Miller, L.H., S.J. Mason, J.A. Dvorak, M.H. McGinniss, and I.K. Rothman 1975 Erythrocyte receptors for Plasmodium knowlesi malaria: Duffy blood group determinants. Science 189:561-563. Molgaard, C.A., E.P. Stanford, D.J. Morton, L.A. Ryden, K.R. Schubert, and A.L. Golbeck 1990 Epidemiology of head trauma and neurocognitive impairment in a multi-ethnic population. Neuroepidemiology 9:233-242.

OCR for page 210
--> Neel, J.V. 1947 The clinical detection of the genetic carriers of inherited disease. Medicine 26:115-153. 1949 The inheritance of sickle cell anemia. Science 110:64-66. 1962 Diabetes mellitus: A "thrifty" genotype rendered detrimental by "progress"? American Journal of Human Genetics 14:353-362. 1976 Diabetes mellitus—A geneticist's nightmare. Pp. 1-11 in The Genetics of Diabetes Mellitus, W. Creutzfeldt, J. Köbberling, and J.V. Neel, eds. Heidelberg, Germany: Springer-Verlag. 1981 The major ethnic groups: Diversity in the midst of similarity. American Naturalist 117:83-87. 1982 The thrifty genotype revisited. Pp. 137-147 in The Genetics of Diabetes Mellitus, J. Köbberling and R. Tattersall, eds. Amsterdam,Netherlands : Academic Press. 1993 Human consanguinity effects revisited: Why is the measurable impact of inbreeding so small? Pp. 58-82 in Genetics of Cellular, Individual, Family, and Population Variability, C.F. Sing and C.R. Hanis, eds. New York: Oxford University Press. Neel, J.V., S.S. Fajans, J.W. Conn, and R. Davidson 1965 Diabetes mellitus. Pp. 105-132 in Genetics and the Epidemiology of Chronic Diseases, J.V. Neel, M.W. Shaw, and W.J. Schull, eds. Washington, DC: Government Printing Office, Publication No. 1163. Neel, J.V., F.M. Salzano, P.C. Junqueira, F. Keiter, and D. Maybury-Lewis 1964 Studies on the Xavante Indians of the Brazilian Mato Grosso. American Journal of Human Genetics 16:52-140. New, M.I., and R.E. Peterson 1967 A new form of congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 27:300-305. Noguchi, S., K. Murakami, and N. Yamada 1993 Apolipoprotein E genotype and Alzheimer's disease. Lancet 342:737. Okuizumi, K., O. Onodera, S. Naruse, H. Tanaka, H. Kobayashi, H. Takahashi, K. Oyanagi, K. Seki, M. Tanaka, H. Fujigasaki, H. Hirasawa, H. Mizusawa, I. Kanazawa, and S. Tsuji 1994 Apolipoprotein E-4 and early-onset Alzheimer's disease. American Journal of Human Genetics 55(suppl.):160(abstract). Oliver, W.J., E.L. Cohen, and J.V. Neel 1975 Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a "no-salt" culture. Circulation 52:146-151. Page, L.B. 1978 Hypertension and atherosclerosis in primitive and acculturating societies. Pp. 1-12 in Hypertension Update, J. C. Hurt, ed. Bloomfield, NJ: Health Learning Systems. Pauling, L. H.A. Itano, S.J. Singer, and I.C. Wells 1949 Sickle cell anemia, a molecular disease. Science 110:543-548. Payami, H., J. Kaye, L.L. Heston, T.D. Bird, and G.D. Schellenberg 1993 Apolipoprotein E genotype and Alzheimer's disease. Lancet 342:738. Pericak-Vance, M.A., P.H. St. George-Hyslop, P.C. Gaskell Jr., J. Growdon, B.J. Crain, C. Hulette, J.F. Gusella, L. Yamaoka, R.E. Tanzi, A.D. Roses, and J.L. Haines 1993 Linkage analysis in familial Alzheimer disease: Description of the Duke and Boston data sets. Genetic Epidemiology 10:361-364. Poduslo, S.E., and J.D. Schwankhaus 1994 Apolipoprotein E alleles in Alzheimer's and Parkinson's patients. American Journal of Human Genetics 55(suppl.):162(abstract). Poirier, J., J. Davignon, D. Bouthillier, S. Kogan, P. Bertrand, and S. Gauthier 1993 Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342:697-699.

OCR for page 210
--> Rao, V.S., C.M. van Duijn, L. Connor-Lacke, L.A. Cupples, J.H. Growdon, and L.A. Farrer 1994 Multiple etiologies for Alzheimer disease are revealed by segregation analysis. American Journal of Human Genetics 55:991-1000. Reaven, G.M. 1988 Role of insulin resistance in human disease. Diabetes 37:1959-1607. Rice, T., M. Province, L. Pérusse, C. Bouchard, and D.C. Rao 1994 Cross-trait familial resemblance for body fat and blood pressure: Familial correlations in the Québec Family Study. American Journal of Human Genetics 55:1019-1029. Roseman, J.N. 1985 Diabetes in black Americans. Pp. 1-24 in Diabetes in America, M.I. Harris and R.F. Hamman, eds. Bethesda, MD: National Institutes of Health, Publication 85-1468. Rotini, C., R. Cooper, G. Cao, C. Sundarum, and D. McGee 1994 Familial aggregation of cardiovascular disease in African-American pedigrees. Genetic Epidemiology 11:397-407. Sahota, A., H.C. Hendrie, K.S. Hall, S. Hui, D.K. Lahiri, M. Farlow, A. Brashear, B.O. Osuntokun, and G.D. Schellenberg 1994 Apolipoprotein E genotypes and Alzheimer's disease in a community-based study of elderly African-Americans. American Journal of Human Genetics 55(suppl.):164 (abstract). Saunders, A., W.J. Strittmatter, D. Schmechel, P.H. St. George-Hyslop, M.A. Pericak-Vance, S.H. Joos, B.L. Rosi, J.F. Gusella, D.R. Crapper-MacLachlan, M.J.Alberts, C. Hulette, B. Crain, D. Goldgaber, and A.D. Roses 1993 Association of apoliporotein E allele 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:1467-1472. Schoenberg, B.S., D.W. Anderson, and A.F. Haerer 1985 Severe dementia: Prevalence and clinical features in a biracial U.S. population. Archives of Neurology 42:740-743. Scotch, N.A. 1963 Sociocultural factors in the epidemiology of Zulu hypertension. American Journal of Public Health 53:1205-1213. Serjeant, G. R. 1985 Sickle Cell Disease. Oxford, England: Oxford University Press. Sims, E.A.H., and P. Berchtold 1982 Obesity and hypertension: Mechanisms and implications for management. Journal of the American Medical Association 24:49-52. Strittmatter, W.J., A.M. Saunders, D. Schmechel, M. Pericak-Vance, J. Enghild, G.S. Salvesen, and A.D. Roses 1993 Apolipoprotein E: High-avidity binding to -amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90:1977-1981. Sutherland, D.J., J.L. Ruse, and J.C. Laidlaw 1966 Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Canadian Medical Association Journal 95:1109-1119. Tattersall, R.B. 1974 Mild familial diabetes with dominant inheritance. Quarterly Journal of Medicine 43:339-357. Tattersall, R.B., and S.S. Fajans 1975 Prevalence of diabetes and glucose intolerance in 199 offspring of thirty-seven conjugal diabetic parents. Diabetes 24:452-462. Tsugi, K., M. Aizawa, and T. Sasasaki 1992 HLA '90-'91. New York: Oxford University Press.

OCR for page 210
--> Vanderpitte, J.M., W.W. Zuelzer, J.V. Neel, and J. Colaert 1955 Evidence concerning the inadequacy of mutation as an explanation of the frequency of the sickle cell gene in the Belgian Congo. Blood 10:341-350. Vogel, F., and A.G. Motulsky 1979 Human Genetics: Problems and Approaches. Berlin, Germany: Springer-Verlag. Ward, R. 1990 Familial aggregation and genetic epidemiology of blood pressure. Pp. 81-100 in Hypertension: Pathophysiology, Diagnosis, and Management , J.H. Laragh and B.M. Brenner, eds. New York: Raven Press. Williams, R.R., S.C. Hunt, P.N. Hopkins, L.L. Wu, and J.M. Lalouel 1994 Evidence for single gene contributions to hypertension and lipid disturbances: Definition, genetics, and clinical significance. Clinical Genetics 46:80-87.