Dissecting Racial and Ethnic Differences
http://www.100md.com
《新英格兰医药杂志》
It is well known that disease does not affect the population equally. Assessing variation in the rates of disease according to demographic factors such as sex and race or ethnicity is the basis of epidemiologic research and affects clinical and public health practice. The basis for such differences — in particular, among self-identified racial and ethnic groups — has recently been the focus of heightened discussion. The concept of race has perhaps triggered the greatest controversy, since it has been used historically to provide support for the mistreatment of one group by another. Also, the assignment of persons of mixed ancestry to one group (e.g., the "one-drop rule" for blacks) instead of recognizing their mixed ancestry undermines any simple formulation of racial categories. At the same time, numerous genetic studies of populations have identified genetic differences among people from different continents that often coincide with racial definitions, although within any population, there remains a great deal of genetic variation.1,2
In this context, it is therefore difficult to discuss the role of genetics in differences among groups, because of the fear that such discourse may reinforce notions of biologic determinism. Some insist that racial and ethnic categories are purely social and devoid of genetic content, or at least of minimal relevance in regard to genetics.3,4 However, recent studies have demonstrated that categories created from random genetic markers correlate very strongly with those based on ancestral continent of origin1 or, within the United States, with self-identified racial and ethnic groups.2 Therefore, a more balanced perspective allows for interactions between genetic and environmental factors in disease causation; both can vary between populations and jointly underlie differences among groups.5
In this issue of the Journal, racial and ethnic differences in a study of the incidence of lung cancer by Haiman et al. take center stage.6 National statistics show that African-American males have an increased incidence of lung cancer, whereas Latino and Asian males and females have reduced rates compared with their white counterparts; women are generally at lower risk than men.7 In a careful analysis of the Multiethnic Cohort Study, Haiman et al. demonstrate striking evidence of an interaction between racial or ethnic group and environment underlying these incidence rates. Their results are summarized in Table 1. The incidence rates for all subjects combined relative to those for whites are similar to those observed previously.7 However, when broken down according to smoking history (those who never smoked, former smokers, and current smokers), the trends differ. Racial and ethnic differences among nonsmokers are attenuated or possibly reversed. On the other hand, relative rates among smokers differ dramatically, with greatly reduced rates among Latinos and Japanese Americans and increased rates among Native Hawaiian men. African Americans also had increased risks.
Table 1. Relative Risk of Lung Cancer among Men and Women, According to Racial or Ethnic Group.
As a group, African-American men had the highest proportion of current smokers and the lowest proportion of subjects who had never smoked, a pattern contributing to their overall excess risk. Likewise, the groups of Latino and Japanese-American women had a lower proportion of current smokers and a higher proportion of those who had never smoked, leading to the reduction in their overall risks. But what explains the reduced incidence among Latino and Japanese-American smokers and increased risk among Native Hawaiian men who smoke? Apparently, it is not entirely the number of cigarettes smoked per day. All groups had lower daily cigarette use than whites, particularly African Americans and Latinos; consistent with a dosage model, the Latino smokers had decreased rates of lung cancer, but the African-American smokers had an increased risk. Similarly, Native Hawaiian men appear to be at increased risk despite smoking fewer cigarettes than whites. Also, the reduction in risk among Japanese-American men appears inconsistent with their nearly similar cigarette consumption. These data suggest an etiologic interaction between race or ethnicity and tobacco exposure, with African Americans and Native Hawaiians more susceptible and Latinos and Japanese less susceptible to the carcinogenic effects of cigarette smoke. Adding to the complexity of the story is the observation that the racial or ethnic patterning among smokers appears to be greatest at the lowest daily dose (fewer than 11 cigarettes per day) and smallest at the highest daily dose (at least 30 cigarettes per day). The authors speculate that factors underlying the ethnic divergence operate more strongly at lower dosages.6
The explanation for the observed racial or ethnic variation remains to be determined. Unmeasured environmental variations, genetic differences, or both may be involved. Dissection of disparities among racial and ethnic groups is complicated by the strong correlation between the socioenvironmental and genetic factors that differentiate these groups, with few persons differentially classified.2,8 However, a number of approaches can be taken. One approach is based on the recognition of mixed continental ancestry among persons self-identified as African American or Latino. This point is also well made by Sinha et al.9 in their letter to the editor in this issue of the Journal. Despite being genetically separable from whites, African Americans show a range of European ancestry that extends from nearly 0 percent to greater than 50 percent.9 Other studies have shown similar trends, with an average of about 20 percent European ancestry.10 Latinos are even more complex, comprising variable proportions of indigenous ancestry from three continental regions (Europe, the Americas, and Africa).11 Within these populations, individual ancestry can be estimated with the use of numerous ancestry-informative genetic markers; once established, this information can be used to examine correlations between the ancestry estimates and the trait of interest.
For example, one could analyze such markers among the African-American and Latino subjects of the Multiethnic Cohort Study and determine the degree to which the incidence of lung cancer and smoking behaviors correlate with European ancestry as compared with African or Native American ancestry. Such analyses are not without caveats, however. Even within an apparently homogeneous admixed group, individual ancestry may remain correlated with environmental risk factors.8 This is most likely to be the case when ancestry is apparent or known, but less likely when it is cryptic. For example, in African Americans, skin pigment is correlated with the degree of European ancestry12 and may therefore lead to residual confounding. Another caveat is that an estimate of individual ancestry from the entire genome may be misleading if the racial or ethnic difference is due to one or a small number of genes.13 However, this is also an attractive scenario, since the same collection of markers could be used to pinpoint specific genetic locations involved in the difference (admixture mapping).10 In this case, the likelihood of residual confounding is reduced.13
Alternatively, mechanisms underlying the metabolism and carcinogenic effect of tobacco smoke can be sought, and racial or ethnic differences studied. For example, some studies report ethnic variation in blood levels of nicotine and cotinine, the byproduct of nicotine, after controlling for cigarette consumption.14 The primary metabolic enzyme cytochrome P-450 2A6 (CYP2A6) shows significant allelic variation among racial and ethnic groups. One null allele (*4) is particularly frequent among the Japanese but not other groups, whereas some deficiency alleles are more frequent among Europeans (*9) or Africans (*17).15 The results of studies of the correlation between deficiency alleles and cigarette consumption and lung cancer have been inconsistent.16 However, a recent twin study showed high heritability of nicotine clearance but only a small contribution of CYP2A6 to that heritability.17 Thus, other, undetermined genes may be involved in this pathway. In any case, specific genetic variants that are causally related to the risk of cancer, if identified, need to be carefully evaluated within the context of the environmental component (e.g., smoking) to assess their joint role in racial or ethnic variation.
Denying the existence of racial or ethnic differences in gene frequencies, some of which may contribute to disease or treatment response, is unlikely to benefit minority populations.8 A good example is provided by the recommendation that patients with colon cancer who are receiving irinotecan undergo genetic testing for homozygosity for deficiency alleles of the enzyme uridine diphosphate glucuronosyltransferase isoform 1A1.18 Homozygotes have severe side effects and a reduction in the starting dose by at least one level of irinotecan is recommended.19 Racial and ethnic variations in the frequency of deficiency alleles should be taken into account when evaluating patients. The *28 deficiency allele is homozygous in approximately 20 percent of African Americans, 15 percent of whites, 1 percent of East Asians, and <0.1 percent of Pacific Islanders.20 In contrast, homozygotes for the *6 deficiency allele occur in approximately 2.5 percent of East Asians but are not found in African Americans or whites.20
On the other hand, for lung cancer, from the perspective of public health it is less clear that genetic analysis offers a useful pathway to a largely socioeconomic problem.21 As Table 1 indicates, eliminating smoking would largely reduce and equalize the rates of lung cancer across the reported racial and ethnic groups.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Institute for Human Genetics, University of California, San Francisco, San Francisco; and the Division of Research, Kaiser Permanente, Oakland, Calif.
References
Rosenberg NA, Pritchard JK, Weber JL, et al. Genetic structure of human populations. Science 2002;298:2381-2385.
Tang H, Quertermous T, Rodriguez B, et al. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet 2005;76:268-275.
Sankar P, Cho MK, Condit CM, et al. Genetic research and health disparities. JAMA 2004;291:2985-2989.
Shields AE, Fortun M, Hammonds EM, et al. The use of race variables in genetic studies of complex traits and the goal of reducing health disparities: a transdisciplinary perspective. Am Psychol 2005;60:77-103.
Olden K, White SL. Health-related disparities: influence of environmental factors. Med Clin North Am 2005;89:721-738.
Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 2006;354:333-342.
National Center for Chronic Disease Prevention and Health Promotion. National cancer data. (Accessed January 6, 2006, at http://www.cdc.gov/cancer/natlcancerdata.htm.)
Risch N, Burchard E, Ziv E, Tang H. Categorization of humans in biomedical research: genes, race and disease. Genome Biol 2002;3:Comment 2007-Comment 2007.
Sinha M, Larkin EK, Elston RC, Redline S. Self-reported race and genetic admixture. N Engl J Med 2006;354:421-422.
Zhu X, Luke A, Cooper RS, et al. Admixture mapping for hypertension loci with genome-scan markers. Nat Genet 2005;37:177-181.
Gonzalez Burchard E, Borrell LN, Choudhry S, et al. Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research. Am J Public Health 2005;95:2161-2168.
Parra EJ, Kittles RA, Shriver MD. Implications of correlation between skin color and genetic ancestry for biomedical research. Nat Genet 2004;36:Suppl:S54-S60.
Mountain JL, Risch N. Assessing genetic contributions to phenotypic differences among `racial' and `ethnic' groups. Nat Genet 2004;36:Suppl:S48-S53.
Benowitz NL, Perez-Stable EJ, Herrera B, Jacob P III. Slower metabolism and reduced intake of nicotine from cigarette smoking in Chinese-Americans. J Natl Cancer Inst 2002;94:108-115.
Nakajima M, Yokoi T. Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metab Pharmacokinet 2005;20:227-235.
Raunio H, Rautio A, Gullsten H, Pelkonen O. Polymorphisms of CYP2A6 and its practical consequences. Br J Clin Pharmacol 2001;52:357-363.
Swan GE, Benowitz NL, Lessov CN, Jacob P III, Tyndale RF, Wilhelmsen K. Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 2005;15:115-125.
Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004;22:1382-1388.
Pazdur R. Changes in Camptosar package insert. Rockville, Md.: Center for Drug Evaluation and Research, 2005. (Accessed January 6, 2006, at http://www.ons.org/fda/documents/FDA80305.pdf.)
Kaniwa N, Kurose K, Jinno H, et al. Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C>T (P229L) found in an African-American. Drug Metab Dispos 2005;33:458-465.
Merikangas KR, Risch N. Genomic priorities and public health. Science 2003;302:599-601.(Neil Risch, Ph.D.)
In this context, it is therefore difficult to discuss the role of genetics in differences among groups, because of the fear that such discourse may reinforce notions of biologic determinism. Some insist that racial and ethnic categories are purely social and devoid of genetic content, or at least of minimal relevance in regard to genetics.3,4 However, recent studies have demonstrated that categories created from random genetic markers correlate very strongly with those based on ancestral continent of origin1 or, within the United States, with self-identified racial and ethnic groups.2 Therefore, a more balanced perspective allows for interactions between genetic and environmental factors in disease causation; both can vary between populations and jointly underlie differences among groups.5
In this issue of the Journal, racial and ethnic differences in a study of the incidence of lung cancer by Haiman et al. take center stage.6 National statistics show that African-American males have an increased incidence of lung cancer, whereas Latino and Asian males and females have reduced rates compared with their white counterparts; women are generally at lower risk than men.7 In a careful analysis of the Multiethnic Cohort Study, Haiman et al. demonstrate striking evidence of an interaction between racial or ethnic group and environment underlying these incidence rates. Their results are summarized in Table 1. The incidence rates for all subjects combined relative to those for whites are similar to those observed previously.7 However, when broken down according to smoking history (those who never smoked, former smokers, and current smokers), the trends differ. Racial and ethnic differences among nonsmokers are attenuated or possibly reversed. On the other hand, relative rates among smokers differ dramatically, with greatly reduced rates among Latinos and Japanese Americans and increased rates among Native Hawaiian men. African Americans also had increased risks.
Table 1. Relative Risk of Lung Cancer among Men and Women, According to Racial or Ethnic Group.
As a group, African-American men had the highest proportion of current smokers and the lowest proportion of subjects who had never smoked, a pattern contributing to their overall excess risk. Likewise, the groups of Latino and Japanese-American women had a lower proportion of current smokers and a higher proportion of those who had never smoked, leading to the reduction in their overall risks. But what explains the reduced incidence among Latino and Japanese-American smokers and increased risk among Native Hawaiian men who smoke? Apparently, it is not entirely the number of cigarettes smoked per day. All groups had lower daily cigarette use than whites, particularly African Americans and Latinos; consistent with a dosage model, the Latino smokers had decreased rates of lung cancer, but the African-American smokers had an increased risk. Similarly, Native Hawaiian men appear to be at increased risk despite smoking fewer cigarettes than whites. Also, the reduction in risk among Japanese-American men appears inconsistent with their nearly similar cigarette consumption. These data suggest an etiologic interaction between race or ethnicity and tobacco exposure, with African Americans and Native Hawaiians more susceptible and Latinos and Japanese less susceptible to the carcinogenic effects of cigarette smoke. Adding to the complexity of the story is the observation that the racial or ethnic patterning among smokers appears to be greatest at the lowest daily dose (fewer than 11 cigarettes per day) and smallest at the highest daily dose (at least 30 cigarettes per day). The authors speculate that factors underlying the ethnic divergence operate more strongly at lower dosages.6
The explanation for the observed racial or ethnic variation remains to be determined. Unmeasured environmental variations, genetic differences, or both may be involved. Dissection of disparities among racial and ethnic groups is complicated by the strong correlation between the socioenvironmental and genetic factors that differentiate these groups, with few persons differentially classified.2,8 However, a number of approaches can be taken. One approach is based on the recognition of mixed continental ancestry among persons self-identified as African American or Latino. This point is also well made by Sinha et al.9 in their letter to the editor in this issue of the Journal. Despite being genetically separable from whites, African Americans show a range of European ancestry that extends from nearly 0 percent to greater than 50 percent.9 Other studies have shown similar trends, with an average of about 20 percent European ancestry.10 Latinos are even more complex, comprising variable proportions of indigenous ancestry from three continental regions (Europe, the Americas, and Africa).11 Within these populations, individual ancestry can be estimated with the use of numerous ancestry-informative genetic markers; once established, this information can be used to examine correlations between the ancestry estimates and the trait of interest.
For example, one could analyze such markers among the African-American and Latino subjects of the Multiethnic Cohort Study and determine the degree to which the incidence of lung cancer and smoking behaviors correlate with European ancestry as compared with African or Native American ancestry. Such analyses are not without caveats, however. Even within an apparently homogeneous admixed group, individual ancestry may remain correlated with environmental risk factors.8 This is most likely to be the case when ancestry is apparent or known, but less likely when it is cryptic. For example, in African Americans, skin pigment is correlated with the degree of European ancestry12 and may therefore lead to residual confounding. Another caveat is that an estimate of individual ancestry from the entire genome may be misleading if the racial or ethnic difference is due to one or a small number of genes.13 However, this is also an attractive scenario, since the same collection of markers could be used to pinpoint specific genetic locations involved in the difference (admixture mapping).10 In this case, the likelihood of residual confounding is reduced.13
Alternatively, mechanisms underlying the metabolism and carcinogenic effect of tobacco smoke can be sought, and racial or ethnic differences studied. For example, some studies report ethnic variation in blood levels of nicotine and cotinine, the byproduct of nicotine, after controlling for cigarette consumption.14 The primary metabolic enzyme cytochrome P-450 2A6 (CYP2A6) shows significant allelic variation among racial and ethnic groups. One null allele (*4) is particularly frequent among the Japanese but not other groups, whereas some deficiency alleles are more frequent among Europeans (*9) or Africans (*17).15 The results of studies of the correlation between deficiency alleles and cigarette consumption and lung cancer have been inconsistent.16 However, a recent twin study showed high heritability of nicotine clearance but only a small contribution of CYP2A6 to that heritability.17 Thus, other, undetermined genes may be involved in this pathway. In any case, specific genetic variants that are causally related to the risk of cancer, if identified, need to be carefully evaluated within the context of the environmental component (e.g., smoking) to assess their joint role in racial or ethnic variation.
Denying the existence of racial or ethnic differences in gene frequencies, some of which may contribute to disease or treatment response, is unlikely to benefit minority populations.8 A good example is provided by the recommendation that patients with colon cancer who are receiving irinotecan undergo genetic testing for homozygosity for deficiency alleles of the enzyme uridine diphosphate glucuronosyltransferase isoform 1A1.18 Homozygotes have severe side effects and a reduction in the starting dose by at least one level of irinotecan is recommended.19 Racial and ethnic variations in the frequency of deficiency alleles should be taken into account when evaluating patients. The *28 deficiency allele is homozygous in approximately 20 percent of African Americans, 15 percent of whites, 1 percent of East Asians, and <0.1 percent of Pacific Islanders.20 In contrast, homozygotes for the *6 deficiency allele occur in approximately 2.5 percent of East Asians but are not found in African Americans or whites.20
On the other hand, for lung cancer, from the perspective of public health it is less clear that genetic analysis offers a useful pathway to a largely socioeconomic problem.21 As Table 1 indicates, eliminating smoking would largely reduce and equalize the rates of lung cancer across the reported racial and ethnic groups.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Institute for Human Genetics, University of California, San Francisco, San Francisco; and the Division of Research, Kaiser Permanente, Oakland, Calif.
References
Rosenberg NA, Pritchard JK, Weber JL, et al. Genetic structure of human populations. Science 2002;298:2381-2385.
Tang H, Quertermous T, Rodriguez B, et al. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet 2005;76:268-275.
Sankar P, Cho MK, Condit CM, et al. Genetic research and health disparities. JAMA 2004;291:2985-2989.
Shields AE, Fortun M, Hammonds EM, et al. The use of race variables in genetic studies of complex traits and the goal of reducing health disparities: a transdisciplinary perspective. Am Psychol 2005;60:77-103.
Olden K, White SL. Health-related disparities: influence of environmental factors. Med Clin North Am 2005;89:721-738.
Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 2006;354:333-342.
National Center for Chronic Disease Prevention and Health Promotion. National cancer data. (Accessed January 6, 2006, at http://www.cdc.gov/cancer/natlcancerdata.htm.)
Risch N, Burchard E, Ziv E, Tang H. Categorization of humans in biomedical research: genes, race and disease. Genome Biol 2002;3:Comment 2007-Comment 2007.
Sinha M, Larkin EK, Elston RC, Redline S. Self-reported race and genetic admixture. N Engl J Med 2006;354:421-422.
Zhu X, Luke A, Cooper RS, et al. Admixture mapping for hypertension loci with genome-scan markers. Nat Genet 2005;37:177-181.
Gonzalez Burchard E, Borrell LN, Choudhry S, et al. Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research. Am J Public Health 2005;95:2161-2168.
Parra EJ, Kittles RA, Shriver MD. Implications of correlation between skin color and genetic ancestry for biomedical research. Nat Genet 2004;36:Suppl:S54-S60.
Mountain JL, Risch N. Assessing genetic contributions to phenotypic differences among `racial' and `ethnic' groups. Nat Genet 2004;36:Suppl:S48-S53.
Benowitz NL, Perez-Stable EJ, Herrera B, Jacob P III. Slower metabolism and reduced intake of nicotine from cigarette smoking in Chinese-Americans. J Natl Cancer Inst 2002;94:108-115.
Nakajima M, Yokoi T. Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metab Pharmacokinet 2005;20:227-235.
Raunio H, Rautio A, Gullsten H, Pelkonen O. Polymorphisms of CYP2A6 and its practical consequences. Br J Clin Pharmacol 2001;52:357-363.
Swan GE, Benowitz NL, Lessov CN, Jacob P III, Tyndale RF, Wilhelmsen K. Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 2005;15:115-125.
Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004;22:1382-1388.
Pazdur R. Changes in Camptosar package insert. Rockville, Md.: Center for Drug Evaluation and Research, 2005. (Accessed January 6, 2006, at http://www.ons.org/fda/documents/FDA80305.pdf.)
Kaniwa N, Kurose K, Jinno H, et al. Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C>T (P229L) found in an African-American. Drug Metab Dispos 2005;33:458-465.
Merikangas KR, Risch N. Genomic priorities and public health. Science 2003;302:599-601.(Neil Risch, Ph.D.)