Critical Perspectives on Racial and Ethnic Differences in Health in Late Life (2004) / Chapter Skim
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Section III--The Search For Causal Pathways8 Genetic Factors in Ethnic Disparities in Health
Section III--The Search For Causal Pathways8 Genetic Factors in Ethnic Disparities in Health
Pages 267-309
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Section III The Search For Causal Pathways
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. Describing the genetic underpinnings of common chronic diseases is a challenge of infinitely greater complexity than obtaining a sequence of nucleotides or finding single gene mutations.
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A second use of race has assumed new relevance. As a label for regional populations, race has a long history in population genetics, and in this arena, important opportunities exist to revisit old questions on interethnic variation in health.
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ETHNIC DISPARITIES IN HEALTH STATUS The focus of this discussion will be on the broad medical syndromes that account for most of the disability and premature mortality in the U.S. population.
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Cause of Death White Black Hispanic Asian All causes 450.4 690.9 432.8 264.6 Heart disease 121.9 183.3 84.2 67.4 Coronary heart disease 79.2 92.5 54.7 42.9 Stroke 23.3 41.4 19.0 22.7 Cancer 121.0 161.2 76.1 74.8 COPD 21.9 17.7 8.5 7.4 Pneumonia/influenza 12.7 17.4 9.8 10.3 Liver disease/cirrhosis 7.1 8.0 11.7 2.4 Diabetes mellitus 12.0 28.8 18.4 8.7 HIV infection 2.6 20.6 6.2 0.8 External causes 46.7 68.8 44.7 24.4 Infant Mortality per 1,000 6.0 13.6 5.8 5.5 Life expectancy 77.3 71.3 >80?
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Potential genetic influences are given considerable attention in studies of prostate cancer, where blacks have an incidence twice that of whites (National Center for Health Statistics [NCHS] , 2000; TABLE 8-2 Death Rates from Malignant Neoplasms in Racial/Ethnic Groups in the United States, 1998 Total*
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Measurement of smoking habits, blood pressure, and cholesterol in young adulthood has been shown to predict directly the quality of life and health care experience of persons over 65 (Daviglus et al., 1998)
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. The blood pressure gap between blacks and whites is narrow in Cuba (Ordunez-Garcia, Espinosa-Brito, Cooper, Kaufman, and Nieto, 1998)
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. The rate of prostate cancer in blacks outside the United States is not yet reliably known, although high rates have been reported from Jamaica (Glover et al., 1986)
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THE CONTRIBUTION OF GENETIC EPIDEMIOLOGY TO UNDERSTANDING ETHNIC DISPARITIES The search for nongenetic explanations of racial/ethnic variation has occupied epidemiologists for many years, and this experience has important implications for the study of genetic factors. Traditionally, epidemiology has placed emphasis on studies that use the individual as the unit of measurement.
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A trait can be highly heritable in each of two popula TABLE 8-3 Methods to Detect Genetic Effects on Interethnic Variation in Health Approach Statistical Method Indirect Heritability The "subtraction method" Molecular Genome scan Candidate genes
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. Because a strong social class effect exists for blood pressure, and blacks and whites differ in socioeconomic status (SES)
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. Noting that blood pressures are higher in "Africans, American Caribbeans and other black populations .
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In addition to the methods that attempt to estimate genetic effects in a semiquantitative way, a substantial literature on racial/ethnic variation in health simply posits a genetic cause and argues that any observed differences could be the explanation. A group of investigators recently justified this approach by pointing out -- correctly -- that it represents accepted practice: "Because of observed group differences in the risk of hypertension .
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. to develop higher blood pressures .
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. Accordingly, over the past decade, genetic epidemiology has shifted its focus dramatically from monogenic to common chronic diseases, driven in large part by the new opportunities for molecular analysis (Collins, Lonjou, and Morton, 1999; Lander, 1996; Lander and Schork, 1994)
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A second, complementary approach postulates candidate genes at the outset, from physiology or animal experimental research primarily, and tests specific variants in these genes. The candidate gene approach can use linkage analysis, based on related individuals, or the case-control design, known in genetic epidemiology as an "association study." Finding Genes: The Genome Scan Approach A broad experience with genome scans now exists, involving traits that range from blood pressure and height to psychiatric disorders (Doris, 2001; Hirschhorn et al., 2001; Laitinen et al., 2001; Levy et al., 2000; Province et al., 2003; Wu et al., 2002)
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A more general problem related to genes and ethnic disparities emerges from this literature. The interpretation of genome scans from various ethnic population samples immediately confronts a dilemma: Should we regard these populations as separate entities?
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. Uncontrolled hypertension is a direct cause of stroke, coronary heart disease, renal failure, heart failure, and vascular dementia.
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Two areas were identified that appeared to influence ACE levels. Subsequently these techniques were applied to a sample of Nigerians and a moderately strong association with blood pressure was confirmed in the same manner (Zhu et al., 2001)
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. To test this hypothesis, microsatellite markers, similar to those used in genome scan analyses, were typed on individuals from eight regional populations and the population structure -- the degree of genetic relatedness of the groups -- was inferred (Wilson et al., 2001)
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. Taken together, these studies suggest that provocative interventions may be more effective at unmasking genetic effects, at least for blood pressure, and open new opportunities to define the role of candidate genes.
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COOPER WHAT IS THIS THING CALLED RACE? As evident from the preceding sections, it is being argued here that race is the organizing principle of the debate over genes and ethnic disparities.
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The genome is conceived of as a fixed, independent cause, projected directly onto the phenotype, without the filtering or conditioning effect of environment. By measuring the distribution of a trait, such as height or blood pressure, we can therefore infer the distribution of the underlying genetic determinants.
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. Thus, although variation among populations exists for some genetic variants, this variation is not aggregated or "packaged" in demographic units, but for the most part occurs piecemeal or random; it is continuous over space rather than occurring in discrete categories (Romualdi et al., 2002)
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Just as the mutations for these monogenic disorders are unequally distributed in ethnic groups, rare variants with large effects on chronic diseases could be spread unevenly in modern populations. However, if the "common disease-common variant" hypothesis is correct, as seems most likely, multiple polymorphisms would have to be present in one population, but absent in others.
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Nonetheless, some of the underlying traits -- such as blood pressure and body composition -- probably were because survival value would be attached to adequate functioning of these systems. Variation in susceptibility to common disease among regional populations therefore could have resulted from differential selective pressure in varying environments.
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TABLE 8-4 Racial/Ethnic Variation in the Prevalence of Sickle Cell Disease Among Live Births, 1990 Racial/Ethnic Group Prevalence* White 2 Black 289 Hispanic, total 5 Hispanic, eastern states 90 Hispanic, western states 3 Asian 7 Native American 36 *
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GENETICS AND THE HEALTH STATUS OF BLACK AMERICANS No discussion of genetic factors and racial/ethnic disparities would be complete without consideration of the contrasts drawn between Africans and non-Africans. The first imperative derives from the undeniable centrality of distinctions between black and white as the basis of the meaning of race.
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. Without taking account of these two complementary forces -- the history of the European encounter with Africa and the intellectual and ideological framework that is used to describe its consequences -- an analysis of the health status of African Americans will continue to substitute justification for explanation.
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The humans who left Africa took with them a sample of the common genetic variants that had been collected through random mutation over our evolutionary history; a more complete repository of these mutations remained in Africa. The assortment of these variants in a given individual provides the sum of genetic risk for a specific chronic disease manifested in the modern industrialized environment.
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Studies of population variation in health status will continue to be constrained if deterministic theories like the "thrifty gene" are applied whenever a disease emerges at a higher prevalence in a new ethnic group. The properties of the genome that make it a single unit shared across all regional populations would be a more appropriate premise for comparative analyses.
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These questions, which can be answered only with molecular data, are now at least "askable." But scientific questions are not asked in a vacuum. Although it can legitimately be argued that in some instances the results of experimentation describe the shape of nature, questions are patently a human construct, made from materials already available to us in the social environment.
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American Journal of Human Genetics, 69, 936-950.
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American Journal of Public Health, 87(2)
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American Journal of Public Health, 82, 1681-1686. Cystic Fibrosis Genetic Analysis Consortium.
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. Patterns of single-nucleotide polymorphisms in candidate genes for blood pressure homeostasis.
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American Journal of Human Genetics, 69, 106-116. Hugot, J.P., Chamailard, M., Zouali, H., Lesage, S., Cezard, J.P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C.A., Gassull, M., Binder, V., Finkel, Y.U., Cortot, A., Modigliani, R., Laurent-Puig, P., Gower-Rousseau, C., Macry, J., Colombel, J.F., Sahbatuou, M., and Thomas, G
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. Evidence for a gene influencing blood pressure on chro mosome 17: Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study.
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. Meta analysis combining genome wide linkage scans from four multicenter networks search ing for human hypertension genes: The Family Blood Pressure Program (FBPP)
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. Racial differences in the relation between blood pressure and insulin resistance.
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gene polymorphisms with ACE concentration and blood pressure. American Journal of Human Genetics, 68, 1139-1148.
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