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© 1996 American Heart Association, Inc.
Articles |
Apolipoprotein E Polymorphism in American Indians and Its Relation to Plasma Lipoproteins and Diabetes
The Strong Heart Study
the Second Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan (S.K.); the Department of Biostatistics and Epidemiology, University of Oklahoma, Oklahoma City (L.D.C., E.T.L.); the Center for Epidemiologic Research, University of Oklahoma Health Sciences Center, Oklahoma City (J.L.Y., O.G.); Medlantic Research Institute, Washington, DC (D.C.R., B.V.H.); Cornell Medical Center, New York, NY (R.B.D.); the National Heart, Lung, and Blood Institute, Bethesda, Md (R.R.F.); and the Aberdeen Area Indian Health Service, Rapid City, SD (T.K.W.).
Correspondence to Dr Barbara V. Howard, Medlantic Research Institute, 108 Irving St, NW, Washington, DC 20010-2933.
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Abstract |
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Apo E is an important genetic factor in the development of cardiovascular disease, which is the leading cause of death among American Indians. We investigated the occurrence of the apo E alleles and the relation between apo E polymorphism and blood lipoproteins and apoproteins in members of 13 American Indian communities in three geographic areas. The frequencies of the
2 alleles in American Indians are significantly lower than those in white Americans, with the lowest frequencies of 2 in American Indians who reside in Arizona. Levels of LDL cholesterol and apo B were highest in those with 4 and lowest in those with 2. Concentrations of HDL cholesterol and apo A-I, however, tended to be lowest in 4 and highest in 2. Concentrations of total and VLDL triglycerides were lowest in the 3 group and higher in groups 2 and 4. Differences in concentrations of LDL cholesterol, HDL cholesterol, apo B, and apo A-I with apo E polymorphism were greater in women than in men, and differences in total and VLDL triglyceride concentrations by apo E phenotype were greater in men. Relations of total and VLDL triglycerides with apo E phenotype were stronger in women after menopause. In addition, differences in nearly all lipid and apoprotein concentrations between postmenopausal women and premenopausal women were greater if they had 2. Relations between apo E phenotype and lipoproteins were seen in individuals with diabetes mellitus as well as in nondiabetics. Apo E was significantly related to glucose control in diabetic women; those with 3 had higher glucose and hemoglobin A1C concentrations. Our findings show that (1) American Indians have low frequencies of apo 2; (2) apo E phenotype can influence levels of VLDL, LDL, HDL, apo B, and apo A-I; (3) the associations of apo E polymorphisms with lipid parameters differ between men and women; and (4) the associations in women of apo E polymorphisms with lipid parameters are modified by menopausal status.
Key Words: lipoprotein • apolipoprotein E • diabetes • cholesterol • American Indians
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Introduction |
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Apo E regulates the metabolism of lipoproteins. The gene for apo E is polymorphic. It has three common alleles,
2, 3, and 4, which code for three major isoforms, resulting in six common genotypes.1 2 Apo E facilitates the binding of triglyceride-rich lipoprotein remnants to receptors that determine their clearance.3 The isoforms vary in their receptor-binding activity, with apo 4 having the greatest receptor binding and apo 2 having a decreased affinity. Individuals with apo 2 have higher levels of triglycerides,4 and apo 2 homozygotes have greatly increased concentrations of remnants, which frequently results in a form of dyslipidemia called type III or dysbetalipoproteinemia. Individuals with 4, conversely, tend to have higher concentrations of LDL cholesterol4 5 6 ; this increase is due, in part, to more efficient absorption of dietary cholesterol and perhaps downregulation of the LDL receptor. Thus, apo E is an important candidate gene for cardiovascular disease.
Several studies have demonstrated a heterogeneity of apo E phenotype frequency among populations.7 Some Northern European populations have significantly increased frequencies of the 4 allele,8 9 and certain Asian populations have been shown to have reduced frequencies of both 2 and 4.10 11 12 13 14 The Strong Heart Study was initiated in 1989 to investigate the prevalence of cardiovascular disease and its risk factors in 4549 American Indians from 13 tribes in three locations. During the course of the first clinical examination (phase 1), the apo E phenotype was determined on all individuals in the study cohort. This provided an opportunity to evaluate the frequency of apo E isoforms in this unique population and to assess the relations between apo E and plasma lipoproteins. Because the frequency of diabetes is very high in these communities, we also explored whether these relations differed in individuals with diabetes.
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Methods |
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Study Population
The study design, survey methods, and laboratory techniques of the Strong Heart Study have been reported previously.15 16 In brief, the study population included members of the following tribes: Pima/Maricopa/Papago Indians of central Arizona who live in the Gila River, Salt River, and Ak Chin communities; the seven tribes of Southwestern Oklahoma (Apache, Caddo, Comanche, Delaware, Fort Sill Apache, Kiowa, and Wichita); and the Oglala and Cheyenne River Sioux in South Dakota and the Devil's Lake Sioux in the Fort Totten area of North Dakota. The study population was enumerated on the basis of tribal council records and a review of the tribal lists by long-time residents to identify people who no longer met the criteria of residence.17
The first (phase 1) clinical examination was conducted between July 1989 and January 1992. The study population consisted of 4549 individuals between the ages of 45 and 74 years: 1500 at the Arizona center, 1527 in Oklahoma, and 1522 in South and North Dakota. Participation rates were 72% in the Arizona center, 62% in the Oklahoma center, and 55% in the Dakota center.15 16 17 Nonrespondents did not differ significantly from respondents in age or self-reported frequency of diabetes, and differences in body mass index and self-reported hypertension were minimal. However, a higher proportion of respondents were women compared with nonrespondents, and a higher proportion of nonrespondents were smokers.17
Clinical Examination
The clinical examination consisted of a personal interview and a physical examination. Participants reported in the morning after at least a 12-hour overnight fast. After informed consent was given, fasting blood samples were obtained for measurements of lipids and lipoproteins (total cholesterol and triglyceride; VLDL, LDL, and HDL cholesterol; and VLDL triglyceride). A 75-g oral glucose tolerance test was performed on all participants except for diabetic persons treated with insulin or oral hypoglycemic agents or those with a fasting glucose 
12.5 mmol/L (225 mg/dL) as determined by an Accu-Check II (Baxter Healthcare Corp).
Lipoproteins were isolated by ultracentrifugation18 ; cholesterol, triglyceride, and glucose were determined by enzymatic methods with a Hitachi chemistry analyzer (Boehringer Mannheim Diagnostics). Insulin was measured by a modification of the method of Morgan and Lazarow19 ; insulin could not be measured in 65 patients with diabetes who showed evidence of anti-insulin antibodies. Total glycated hemoglobin was measured by high-performance liquid chromatography.20 As described in depth previously,21 apo E phenotype was determined in whole plasma by a modification of the method of Kamboh et al,22 in which 2 hours of isoelectric focusing are followed by immunoblotting to visualize the apo E bands.
Anthropometric measurements included weight, height, and waist and hip circumferences. Percent body fat was estimated with an RJL Impedance Meter (model B14101, RJL Equipment Co) utilizing an equation based on total body water.23 Three consecutive measurements of blood pressure, based on the first and fifth Korotkoff sounds, were performed on the right arm of seated participants after 5 minutes of rest, using the appropriate size cuff with a Baum mercury sphygmomanometer (WA Baum Co). The mean of the last two measurements was used to estimate the blood pressure. A 12-lead ECG was taken with a Marquette system (MAC-PC or MAC-12, Marquette Electronics). All ECGs were read by three staff cardiologists at the Fitzsimons Medical Center and were forwarded to the University of Minnesota ECG center for application of Minnesota codes.24 Questions administered during the interview assessed demographic information; family health history; and lifestyle and medical history, including the Rose questionnaire for angina pectoris.25
Persons were classified as diabetic according to World Health Organization criteria26 if they were taking insulin or oral antidiabetic medication or if they had fasting glucose concentrations >7.8 mmol/L (>140 mg/dL) or 2-hour glucose concentrations >11.1 mmol/L (>200 mg/dL) after a 75-g oral glucose tolerance test. In this analysis, the nondiabetic group included those with normal glucose tolerance, defined as fasting and 2-hour glucose <7.8 mmol/L (<140 mg/dL), and those with impaired glucose tolerance, defined as fasting glucose <7.8 mmol/L (<140 mg/dL) and 2-hour glucose between 7.8 and 11.0 mmol/L (140 and 199 mg/dL).
Based on their responses during the personal interview, women were classified as postmenopausal if they reported complete menstrual cycle cessation. Use of estrogen (excluding birth control pills) was classified as never, past, or present. The terms "premenopausal" and "postmenopausal" are used to refer to different women, not to the same women before and after menopause.
The significance of center-specific differences and differences in lipids and lipoproteins by apo E phenotype was evaluated by ANOVA. For the analysis of associations with apo E phenotype, individuals were combined in three groups: group 2 (E2.2 and E3.2), group 3 (E3.3), and group 4 (E4.3 and E4.4); the individuals (n=131) with E4.2 were not included. Statistical procedures were performed by use of the SAS statistical program (SAS Institute Inc).
The average effect (
) of the 2, 3, and 4 alleles was determined by use of the following formulas 27 :
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2 through f4 are the allele frequencies; µ22 through µ44 are means for the phenotype, adjusted for age, body mass index, and menopausal status28 29 ; and µ represents the grand mean of the sample.30 For this analysis, all phenotypes were included, and they were not grouped. |
Results |
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Table 1
summarizes the pertinent characteristics of the study population by center. Participants ranged in age from 45 to 74 years, with a greater proportion of women than men examined at each center. Diabetes occurred with a high frequency among study participants, with the highest frequency in Arizona.
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The distribution of apo E phenotypes by center and sex is shown in Table 2. The E2.2 and E3.2 phenotypes were very uncommon in all three centers, especially in Arizona. The majority of participants in all three centers were apo E3.3. Apo E4.3 averaged 
25% in Arizona and Oklahoma and 20% in South and North Dakota. Phenotypes E4.2 and E4.4 were very uncommon in the three centers.
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The distribution of apo E allele frequencies by center and sex is shown in Table 3 compared with data from four studies of whites.4 5 30 31 Compared with whites, American Indians have a higher frequency of 3 and a much lower frequency of 2 alleles. The differences were observed in all three centers, although Oklahoma and South and North Dakota participants had a somewhat higher frequency of the 2 allele than did those in Arizona, and the Dakota residents had a somewhat lower frequency of 4 than did the other two centers. Neither the distribution of phenotypes nor allele frequencies differed significantly by sex.
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Because of the effect of diabetes on lipoproteins, the relations between apo E phenotype and plasma lipoproteins were analyzed separately in those with and without diabetes (Table 4). Phenotypes were condensed into three groups: group 2 (E2.2 and E3.2), group 3 (E3.3), and group 4 (E4.3 and E4.4). The subjects with E4.2 were not included. In nondiabetic women, LDL cholesterol was significantly related to apo E phenotype, with those with E4 having higher concentrations than those with E2. In nondiabetic women, there was also a significant relation between apo E phenotype and HDL; those with E4 had lower concentrations of HDL cholesterol than did those with E2. In nondiabetic women and men, mean levels of total and VLDL triglycerides were lowest in those with the apo E3 phenotypes and higher in those with E2 or E4, with differences greater in men than in women. The variances (as indicated by the standard deviation) of total and VLDL triglycerides increased from E2 to E4 in nondiabetic men and women. In nondiabetic men, LDL was lowest in the E2 group, but the difference across apo E groups was not significant. There was no statistically significant relation between apo E phenotype and HDL cholesterol in nondiabetic men.
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There were similar patterns of apo E phenotype and lipoprotein levels in individuals with diabetes, with the exception that the increase in LDL over apo E groups reached significance in diabetic men.
Apo E2 was associated with lower apo B and apo E4 with higher apo B (Table 4
). The relation between apo E phenotype and apo B concentrations was significant in nondiabetic women and in diabetic women and men. Apo E was significantly related to apo A-I in nondiabetic women, with the highest levels in those with E2 and the lowest levels in those with E4. There was a similar but nonsignificant trend in diabetic women.
After exclusion of women using oral contraceptives and those classified as current estrogen users (n=212), women were separated into premenopausal and postmenopausal groups (Table 5). Data are presented for nondiabetic women. The patterns of differences in LDL, HDL, apo B, and apo A-I by apo E phenotype were similar in premenopausal and postmenopausal women, but the differences in total and VLDL triglycerides among apo E groups were larger in postmenopausal women. When differences in mean lipoprotein levels between premenopausal and postmenopausal women were computed for each apo E group, greater differences for total and LDL cholesterol and total and VLDL triglycerides were seen in those with the 2 allele than in those with 4.
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The associations of apo E phenotype with glucose tolerance and insulin concentrations also were explored (Table 6). There was an association between apo E phenotype and 2-hour glucose in nondiabetic women and with fasting glucose and hemoglobin (Hb) A1C in diabetic women; there was no relation between fasting glucose and apo E in men. Furthermore, there were trends for 2-hour glucose and HbA1C for nondiabetic men. There were no relations between apo E and plasma insulin in diabetic women or in men, although a significant trend was found in nondiabetic women.
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The average effects (µ) of the 2, 3, and 4 alleles on LDL, HDL, total triglycerides, apo B, and apo A-I after adjustment for diabetes, age, body mass index, and menopausal status are shown in Figs 1 and 2. For these computations, phenotypes were not grouped, and all were included. The results confirm the trends with E phenotype and the sex differences suggested in Table 4; changes across E groups were significant for LDL, HDL, apo B, and apo A-I in women and for total triglycerides and apo B in men.
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Discussion |
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This study has afforded the opportunity to evaluate the frequency of apo E alleles in American Indians and to examine both the possible controlling influence of apo E on lipoprotein concentrations and the potential modifying influence of diabetes on these associations. Because the Strong Heart Study involves 13 American Indian communities in three geographic areas, it provides a unique mechanism for examination of the associations with apo E phenotype over a broad range of American Indian groups.
The study results indicate that the 2 allele occurs with less frequency among American Indians than in whites and that the 3 allele is more frequent. The presence of ethnic differences in distribution of apo E alleles has been postulated for some time based on smaller, non–population-based samples.7 This phenomenon has now been confirmed by this population-based study. Data from China11 13 and Japan10 12 14 suggest that other populations of Asian origin also have lower prevalences of apo E2 phenotype compared with whites. In our study, the 2 allele showed the lowest frequency among Strong Heart Study participants from the Arizona center. This, in combination with the finding that the degree of non-Indian admixture was lowest in Arizona,28 suggests that the occurrence of 2 may reflect the degree of genetic admixture with non-Indian groups and that 2 may have been virtually nonexistent in ancestors of American Indians. In a study of apo E phenotypes in another Amerindian population, Mayans on the Yucatan Peninsula,32 2 was completely absent.
Measures in our laboratory of a population-based sample of 4000 blacks and whites also showed significant ethnic differences, with higher frequencies of 2 and 4 alleles among blacks than among whites (12.7% versus 7.9% for 2 and 20.7% versus 12.5% for 4).31
There were several allele effects of apo E on plasma lipoproteins and apoproteins in American Indians. Despite their low average levels of LDL cholesterol,27 American Indians with the apo 4 allele appear to have higher levels of LDL, and those with apo 2 have lower concentrations. The effect of apo E isoforms on LDL concentrations, described in multiple populations, is thought to be mediated by at least two mechanisms. Because the apo 2 allele is thought to have less affinity for the receptor that governs the uptake of VLDL remnants, individuals with 2 would be expected to have lower intracellular cholesterol in hepatocytes and thus upregulated LDL receptors and lower plasma concentration. A second possibility is that hepatic receptors for LDL have increased availability because of the lack of competition for binding by remnants of triglyceride-rich lipoproteins.
Apo E is also associated with HDL cholesterol in American Indians, a relation significant in women but not in men. The relation between apo E polymorphism and HDL has been reported in some studies33 34 but not in others,30 and the mechanism of this relation remains to be clarified. Recently, in vivo35 and in vitro36 studies have shown that apo E plays an important role in the regulation of cholesterol ester transfer protein. Thus, if apo E polymorphism affects cholesterol ester transfer protein activity, this may explain the relation between apo E polymorphism and HDL concentrations. Another possibility is that apo E may be involved in the extracellular efflux of cholesterol.37 If the efflux rate varies with apo E phenotype, then it might have a corresponding effect on HDL concentrations. Finally, it has been suggested that apo E modulates lipoprotein lipase activity,38 and individuals with higher lipoprotein lipase activity might be expected to have higher concentrations of HDL. Whatever the mechanism, it remains to be explained why the effects on HDL are more pronounced in women, especially in premenopausal women.
Concentrations of total and VLDL triglycerides appear to have more complex relations with apo E, and persons with 2 or 4 alleles have higher concentrations than do individuals with apo 3. This U-shaped trend has been reported in whites,4 30 blacks,31 and Mexican Americans.39 The association of apo 2 with higher concentrations of triglycerides would be expected, because remnants of triglyceride-rich lipoproteins would be cleared more slowly in these individuals. The mechanism that produces elevated triglycerides in individuals with 4 is less clear. As discussed above, individuals with 4 have lower lipoprotein lipase activity, which could explain both the higher triglycerides and lower HDL in these individuals. We also observed an association between apo E and the variability of total and VLDL triglycerides. An increased variance of triglycerides in persons with apo 4 has been reported by Reilly et al.6 Interestingly, variance of total and VLDL triglycerides was highest with apo 3 in those with diabetes.
The results of this study indicate that there are sex differences in the relationship of apo E polymorphism to plasma lipid levels. In men, there were greater changes in total and VLDL triglycerides with apo E polymorphism. There was no significant association in men between apo E and HDL, and the changes in LDL with apo E in men were smaller. In contrast, in women, apo E polymorphism was significantly related to plasma LDL, HDL, and apo B and apo A-I concentrations. A greater effect of 4 allele on LDL in white women was also observed by Xhignesse et al,5 and Reilly et al40 reported a larger number of correlations between apo E polymorphism and lipid and apoprotein traits in white women. In contrast to data reported previously,24 postmenopausal women, compared with premenopausal women in the American Indian population, did not show a greater influence of apo E phenotype on LDL cholesterol, although they did show greater differences in triglycerides with apo E phenotype. Of interest was the observation that menopause-associated differences in lipoproteins are greater in those women with 2. The biggest increases in LDL and triglycerides were seen for postmenopausal women with the E2.2/3.2 phenotypes. Thus, it appears that the favorable lipoprotein profile associated with the 2 allele, ie, lower LDL and higher HDL, is less pronounced after menopause.
Sex hormones are known to have multiple effects on lipoprotein metabolism. The shortened retention time of apo E in VLDL associated with the presence of estrogen, as reported in animal studies,41 suggests that estrogen influences VLDL clearance. Sex hormones also are known to influence enzymatic activities, with hepatic lipase being stimulated by testosterone.42 Thus, the magnitude of the sex differences in levels of LDL, VLDL, and HDL by apo E phenotype may very well be determined by the modulating effects of hormones on the processes that control these lipoproteins. In premenopausal women, the effect of estrogen on lowering LDL may influence the effects of the apo E phenotype. Conversely, the absence of estrogen in postmenopausal women raises VLDL concentrations, which may influence the effects of apo E on VLDL metabolism. The different interaction of apo E and menopause with LDL between white and American Indian women may be related to the much lower LDL concentrations among the American Indian population.
Because there is such a high prevalence of diabetes among American Indian communities and because diabetes is known to have multiple influences on plasma lipoproteins, we examined the possible associations with apo E phenotype separately in individuals with diabetes. In general, similar associations of apo E with lipoprotein concentrations were observed in diabetic and nondiabetic individuals. Of interest was the apparent association of apo E with glucose control in women, with HbA1C and glucose concentrations somewhat worse in diabetic women with the E3 phenotype. We observed a relation between apo E phenotype and plasma insulin in nondiabetic women (with levels highest in women with apo E4). Similar increases in insulin in individuals with apo E4 were observed in Mexican Americans and whites in the San Antonio Heart Study.39 The associations of glucose and insulin with apo E phenotype should be explored in other populations.
In summary, this study has demonstrated that American Indian populations have lower frequencies of apo 2 and higher 4 alleles than do whites. Furthermore, there were significant associations of apo E phenotype with concentrations of several lipoproteins and apoproteins among American Indians, especially in women. These associations were observed even among those with diabetes. Apo E4 was associated with higher concentrations of LDL, lower concentrations of HDL, and higher concentrations of triglycerides, a constellation of changes that would enhance the atherogenicity of lipoprotein profiles in this population, which otherwise has generally favorable LDL concentrations. Apo E must thus be considered a possible contributor to atherogenesis in American Indians, especially in women.
This unique population is characterized by a high prevalence of insulin resistance, obesity, and diabetes.28 29 Overall prevalence of coronary heart disease in the Strong Heart Study cohort is somewhat lower than in other US populations, but there are major differences between the centers in coronary heart disease, with American Indians in Arizona having low rates and those from the Dakota centers having the highest.16 Coronary heart disease was most strongly related to diabetes and the presence of diabetes-associated risk factors such as hypertension, albuminuria, and low HDL. It remains to be determined, as this cohort of American Indians is followed, how apo E phenotype is related to coronary heart disease.
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Acknowledgments |
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The authors acknowledge the assistance and cooperation of the Ak Chin Papago/Pima, Apache, Caddo, Cheyenne River Sioux, Comanche, Delaware, Devil's Lake Sioux, Fort Sill Apache, Gila River Pima/Maricopa, Kiowa, Oglala Sioux, Salt River Pima/Maricopa, and Wichita Indian communities, without whose support this study would not have been possible. The authors also wish to thank the Indian Health Service hospitals and clinics at each center, as well as Betty Jarvis, Martha Stoddart, and Beverly Blake, directors of the Strong Heart Study clinics, and their staffs; and to acknowledge the assistance of Ellen Shair in the preparation of the manuscript and the secretarial assistance of Ruth Ross-Hunley. This study was conducted under cooperative agreement grants (U01-HL-41642, U01-HL-41652, and UL01-HL-41654) from the National Heart, Lung, and Blood Institute. The views expressed in this article are those of the authors and do not necessarily reflect those of the Indian Health Service.
Received September 12, 1995;
revision received March 1, 1996;
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