© 1997 American Heart Association, Inc.
Articles |
Association of Apo E Polymorphism With Plasma Lipid Levels in a Multiethnic Elderly Population
From the Division of General Medicine, College of Physicians & Surgeons (A.P.-M., S.S.); Division of Epidemiology, School of Public Health (A.P.-M., R.M., S.S.); Gertrude H. Sergievsky Center, College of Physicians & Surgeons (R.M.); and Division of Preventive Medicine, College of Physicians & Surgeons (L.B.), Columbia University, New York, NY.
Correspondence to Dr Lars Berglund, Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, 630 W 168th St, P&S 9–510, New York, NY 10032-3702. E-mail berglun{at}cudept.cis.columbia
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Abstract |
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Abstract Apolipoprotein E polymorphisms are important determinants of blood lipid levels and have been associated with longevity and atherosclerosis. However, information is limited on the effects of apo E variation on the lipids of nonwhite and elderly individuals. We tested the hypothesis that apo E polymorphisms are associated with plasma lipid levels in an elderly, multiethnic population. Cross-sectional data from 1068 noninstitutionalized individuals from northern Manhattan over the age of 64 who were not on a lipid-lowering diet or drug were analyzed. The ethnic distribution was 34% African-Americans, 47% Hispanics, and 19% non-Hispanic Caucasians. In the entire group, the most prevalent apo E allele was
3 (76%), followed by 4
(16%) and 2 (8%); 4 was more prevalent in African-Americans
(21%) than in non-Hispanic Caucasians (12%) or Hispanics (14%). The
apo 2 allele was the most important correlate of plasma lipids,
but this association varied across ethnoracial groups. After being
adjusted for age, sex, obesity, diabetes mellitus, and alcohol intake,
LDL cholesterol levels declined with each apo 2
allele by 8.8 mg/dL in Hispanics and by 25.6 and 18.1 mg/dL in
non-Hispanic Caucasians and African-Americans, respectively
(P<.001). No significant independent effect was noted
for any apo E genotype on HDL cholesterol. Overall,
there was a reduction in the total/HDL cholesterol ratio,
per apo 2 allele, of 0.82 in non-Hispanic Caucasians and 0.43
and 0.48 in African-American and Hispanic individuals, respectively
(P<.05). In a multivariate model, apo
4 did not significantly affect plasma lipid levels. Plasma
triglyceride levels were inversely correlated with the
number of apo 4 alleles (175, 159, and 143 mg/dL with 0, 1, and
2 alleles, respectively; P =.002), and this effect
increased with age. Thus, in an elderly, multiethnic population,
apolipoprotein E polymorphisms were important determinants of blood
lipids, with differing effects depending on ethnicity. The presence of
apo 2 was associated with lower LDL cholesterol levels
and total/HDL cholesterol ratio, although apo
genotype did not influence HDL cholesterol levels.
Prospective studies are needed to test whether apo 2 protects
against incident cardiovascular disease in the
elderly.
Key Words: epidemiology • genetics • apo E • serum lipids • elderly
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Introduction |
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Plasma cholesterol and other lipid levels increase from early adulthood through late middle age but decline after age 70.1 2 3 Although the association is progressively attenuated with age,4 5 6 the absolute risk of coronary heart disease (CHD) attributable to blood lipids increases in spite of the decrease in lipid levels.5 7 8 Among the elderly, the impact of LDL cholesterol levels has not been established to the same extent as it has in younger people. Instead, the HDL fraction of plasma cholesterol has been found in several studies to be an important protective factor against CHD in the elderly.9 10 This can be expressed as a favorable total cholesterol/HDL cholesterol ratio, which under normotriglyceridemic conditions is affected primarily by HDL cholesterol and LDL cholesterol levels.
Apolipoprotein (apo) E polymorphisms have been associated with
variations in blood cholesterol level and with the risk of
atherosclerosis and premature
cardiovascular disease.11 12 13 14 15 16 17 18 19 20 As
much as 16% of the genetic variance (8% of total variance) of LDL
cholesterol can be accounted for by the apo E locus, a
contribution unsurpassed by any other gene in the general
population.13 21 22 Of the apo E alleles,
3 is the most common, with a phenotype prevalence of 67% to
87%.13 17 The apo 4 allele frequency is
about 14% in US non-Hispanic Caucasians13 and
10% in U.S. Hispanics,23 but it is considerably
higher in African-Americans.24 25 26 People who
carry the apo 2 and 4 alleles have, respectively, lower and
higher total plasma cholesterol than those with the apo
3/3 genotype.13 27 28 The prevalence
of apo 4 decreases with age, and it has been suggested that the
increased LDL cholesterol levels among 4-carriers could
contribute to its negative impact on
longevity,17 29 30 31 32 33 34 although other factors might
also contribute. So far, although a number of studies have documented
the relationship of the apo E locus to plasma lipids in non-Hispanic
Caucasians, fewer studies have been performed in elderly or
African-American and Hispanic individuals. In the present study, in
an elderly multiethnic population living within a similar environment,
we tested the hypothesis that apo E polymorphisms are associated
with plasma lipids in the elderly and that the degree of the
association varies across race/ethnicity.
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Methods |
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Subjects
Apo E genotype analysis was performed on 1599 individuals who were randomly selected from Medicare beneficiaries aged 65 years or older residing in northern Manhattan. For the analysis of apo E polymorphisms and plasma lipids, we excluded 531 individuals (33%) for the following reasons: 162 were on low-calorie/fat diets, either by their own choice or by prescription because of a variety of clinical conditions; 190 were on estrogen or lipid-lowering treatment (the majority of these subjects were also on low-fat diets); and fasting lipid measurements were not available for 179 individuals. Therefore, the study is based on 1068 individuals for whom both fasting lipid levels and apo E genotype were assessed.
Analytical Procedures
Blood samples were drawn in EDTA-containing tubes after an
overnight fast. Plasma levels of total cholesterol and
triglycerides were determined using standardized enzymatic
procedures (Boehringer Mannheim) in a Hitachi 705 automated
spectrophotometer. HDL cholesterol was analyzed
after precipitation of apo B–containing lipoproteins with
phosphotungstic acid.35 LDL
cholesterol levels were calculated by using the Friedewald
formula.36 In 29 individuals (2.7% of the
subjects), triglyceride levels >400 mg/dL precluded
estimation of LDL cholesterol levels. Our laboratory
participated in the Centers for Disease Control Lipid Standardization
Program, and interassay coefficients of variation were 2% for
cholesterol and triglycerides and 3% for HDL
cholesterol. Genotyping of apo E was carried out from
genomic DNA essentially as described by Hixson and
Vernier.37
Plasma total cholesterol, LDL cholesterol, HDL cholesterol levels, and triglycerides were the dependent variables in this analysis, as well as the total/HDL cholesterol ratio. This ratio is particularly relevant in the elderly as a measure of risk for CHD compared to total cholesterol or LDL cholesterol levels,9 10 38 39 and it takes into account the fact that a given factor may impact on HDL cholesterol as well as the proatherogenic forms of cholesterol.40 41 42 Covariates that were considered in the models included age, sex, race/ethnicity, body mass index (BMI=weight (kg)/height (m)2), history of diabetes mellitus, and alcohol intake, which were telephonically ascertained (in English or Spanish) by using the Willett Semiquantitative Food Frequency Questionnaire.43
Statistical Methods
Data management and statistical analysis were conducted
in SPSS for Windows 6.0.44 Descriptive statistics
were used for patient population characteristics; frequency
distributions were examined, and improbable values were noted. The
distributions of plasma lipid values were not normal but
positively skewed; accordingly, a logarithmic transformation was
applied to these variables, except for plasma
cholesterol and LDL cholesterol, the values of
which were square-root transformed to achieve near-normal
distributions. The results of the analyses, however, did not
change appreciably when original, untransformed values were used, and
these are presented for ease of interpretability. In some
analyses, plasma lipid levels were adjusted for age, sex, and
race/ethnicity by regressing the values of each lipid
parameter on these demographic characteristics and adding
the residuals to the mean lipid value. Plasma lipid levels were
compared with the ANOVA test; linear trend values of P were
obtained in testing the number of specific apo alleles. Values
of P are two-sided and not adjusted for multiple
comparisons.
Finally, we used multivariate modeling to test the
association between apo E genotypes and the plasma lipids that
were measured. Multiple linear regression analyses were
conducted for each lipid by entering in each model apo E alleles
(3 was dropped because of high collinearity with 2 and 4),
sex, age group, race/ethnicity, BMI, alcohol intake, and diabetes
mellitus, as well as terms representing significant
multiplicative interactions of these variables, by additional
stepwise methods (P<0.05). Stratified models were fitted
for each stratum of race/ethnicity and age group as important
interactions were discovered for some of the lipid measures
(P<0.01). The regression assumptions of these models were
examined by using residual
diagnostics.45
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Results |
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Two thirds of the study subjects were women, and the mean age of the group was 75.7 years (11% were 85 years or older). Reflecting the overall population in northern Manhattan, non-White individuals dominated; almost half were Hispanics, and 30% were African-American. In the studied group, the most prevalent apo E allele was
3
(75%), followed by 4 (15.5%) and 2 (9.6%). The allele
distribution among the 531 individuals excluded was similar for apo
3 (78.5%) and 4 (15.7%), although the prevalence of apo 2
was somewhat lower (5.7%, P<0.001). Overall, there were
only minor demographic differences between studied and excluded
subjects: the excluded subjects were slightly younger (mean age: 74.4
versus 76.5 years), females weremore common (74% versus 66%),
and for race/ethnicity there was no difference in the frequency for
Hispanics, although non-Hispanic Caucasians were more common (28%
versus 19%). These differences reflect the exclusion criteria defined
above. As seen in Table 1
, for the
studied group, the apo E distribution varied among the ethnoracial
groups. The prevalence of the apo 4 (20.2%) allele was
significantly higher in African-Americans, and the apo 2 allele
frequency (11.7%) also tended to be higher in this group. The apo E
allele distribution was similar in Hispanics and non-Hispanic
Caucasians. There was no difference in the apo E distribution between
men and women. Although the variation in apo E allele frequency
with age was not significant, there was a trend toward a lower
prevalence of apo 4 (12.3%) among individuals over 84 years of age
(compared to 16.0 in younger individuals); all 24 4/4 homozygotes
were younger than 85 years (P=0.04). There was no
significant difference in age distribution among the three race/ethnic
groups, a finding arguing against a possible selective survival of one
of the groups. The lack of association between apo E polymorphisms
and sex or age persisted across strata of each other and
race/ethnicity; likewise, the higher prevalence of apo 4 alleles
in African-American individuals was consistent across sex and
age groups (stratified data not shown).
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There was no association between apo E polymorphisms and behavioral
factors such as dietary fat intake, alcohol consumption, smoking, or
physical activity. Nor was association found between apo E allele
distribution and prevalence of comorbidities such as diabetes mellitus,
hypertension, coronary artery disease, or stroke. Apo 4 was
more prevalent among the 26% of study subjects who had a diagnosis of
dementia (35% versus 27%, P=0.004), yet lipid levels and
the correlations between apo E polymorphisms and plasma lipids were
similar across dementia. The rate of dementia in the
present study was slightly higher than that in other studies, but
the present rate has been substantiated in follow-up
studies.46
Table 2 illustrates the distribution of
plasma lipids across race/ethnicity and other demographics. Total and
LDL cholesterol levels were lower among Hispanics;
African-American individuals had higher HDL cholesterol and
lower triglyceride levels than the other groups. The
total/HDL cholesterol ratio was 4.52 overall, and it was
significantly lower in African-Americans, in women, and in individuals
over 85 years of age. In all ethnic groups, increasing age was
accompanied by lower triglycerides.
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Table 3 shows mean plasma lipid levels
adjusted for age, sex, and race/ethnicity across apo E
phenotype and number of specific alleles. The total/HDL
cholesterol ratio was inversely associated with the number
of apo 2 alleles (P<0.0001). This association was
explained principally by the effects of apo 2 on LDL
cholesterol, the levels of which decreased markedly with
the number of apo 2 alleles. In addition, the number of apo 2
alleles was positively associated with HDL cholesterol
levels, and that of apo 3 was inversely associated. The number of
apo 4 alleles was directly associated with LDL
cholesterol but not with HDL cholesterol, and
it had no association with the total/HDL cholesterol ratio
either with or without exclusion of individuals with apo 2
alleles. The number of apo 4 alleles, however, was inversely
related to the level of triglycerides. Notably, apo 2,
which has been associated with disturbances of
triglyceride metabolism, did not correlate with
fasting triglyceride levels in the study group as a whole
or among individuals in the top 40% of dietary fat intake (data not
shown). There was a significant increase in LDL cholesterol
levels from 2- to 4-carriers in both men and women and in all
three age groups (Table 4). However,
among Hispanics, this difference was not significant among men but was
significant in women.
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Multiple linear regression analyses were conducted separately
for each lipid fraction, entering in each model apo 2 and 4
alleles, sex, age group, race/ethnicity, BMI, alcohol intake, and
diabetes mellitus. Significant interactions were detected between apo E
isoforms and age group for triglycerides and between apo E
isoforms and race for the other plasma lipids (P<0.01).
Table 5 shows the results for each of
these strata. The most prominent effects were seen for total and LDL
cholesterol levels. LDL cholesterol declined
with each apo 2 allele by 8.8 mg/dL in Hispanics and by 25.6
mg/dL and 18.1 mg/dL in non-Hispanic Caucasians and African-Americans,
respectively (P<0.001). As seen in Fig 1, the 2-effect was very similar in
African-Americans and non-Hispanic Caucasians and considerably less
pronounced in Hispanics. This effect on LDL cholesterol
levels was accompanied by a reduction in total/HDL
cholesterol ratio, per apo 2 allele, of 0.82 in
non-Hispanic Caucasians, and of 0.43 and 0.48 in African-American and
Hispanic individuals (values of P <0.05). No significant
independent effect was noted for any apo E genotype on HDL
cholesterol, although a positive trend was noted for apo
2 in non-Hispanic Caucasians and Hispanics. Interestingly, in this
elderly population, there was no significant effect of the apo 4
allele on LDL cholesterol or total
cholesterol levels independent of apo 2 and the other
covariates in the model (Table 5). The plasma triglyceride
level was inversely correlated with the number of apo 4 alleles,
and this effect, although not statistically significant, increased with
age.
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Discussion |
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The main finding of this study is that the number of apo
2
alleles was the most important correlate of plasma lipids in our
triethnic sample of elderly subjects, and the effect of the 2
allele varied across ethnoracial groups. The number of apo 2
alleles was inversely correlated with LDL cholesterol
and the total/HDL cholesterol ratio. The association
between apo 2 alleles and LDL cholesterol levels was
considerably less pronounced among Hispanics than among
African-Americans or Caucasians (Fig 1
). The number of apo 4
alleles was associated with LDL cholesterol levels in
crude analysis (except in non-Hispanic Caucasians) and
inversely correlated with plasma triglycerides among the
oldest individuals. However, in multivariate
analyses, only the effects of the apo 2 allele remained
independently significant. Although the effect of apo E
genotypes on blood lipids varied across race/ethnicity, apo E
genotypes did not explain the lipid differences between the
ethnoracial groups.
In a prospective cohort of the Established Populations for
Epidemiologic Studies of the Elderly, an increase in 1 U of the
total/HDL cholesterol ratio was associated with a 17%
increase in coronary heart disease in subjects aged 71 years
and older (95% CI, 9% to 26%).9 This finding
illustrates the clinical importance of understanding the role of the
apo 2 allele in explaining variability in plasma lipid levels in
the elderly. We found at least one apo 2 allele in 18% of this
multiethnic elderly population, and homozygous subjects had a total/HDL
cholesterol ratio up to 1.8 times lower than those without
apo 2 alleles. Apo E polymorphisms, however, influenced LDL
cholesterol levels rather than the clearly beneficial HDL
cholesterol levels. In younger adults, the lower LDL
cholesterol level of apo 2 subjects is frequently
counterbalanced by a higher level of plasma
triglycerides.27 In this multiethnic
elderly population, however, apo 2 was not accompanied by a
significant increase in triglyceride levels. This
observation argues against the possibility that VLDL
cholesterol levels increased as LDL cholesterol
decreased. The demonstration that the proatherogenic lipoprotein
fractions decreased with increasing number of apo 2 alleles thus
suggests that the apo 2 allele may confer protection against
cardiovascular disease in the elderly.
In a large number of clinical studies, an association between apo E
polymorphisms and CHD has been
demonstrated.13 14 15 16 17 18 19 20 This association has been
mostly manifested by an increase in the apo 4 allele frequency,
with a concomitant increase in LDL cholesterol levels. The
underlying mechanisms for the atherogenic effects of apo E
polymorphisms have not been clarified, although several
possibilities have been suggested. Metabolic studies have
demonstrated a decreased catabolism of LDL particles in apo 4
carriers, and apo E polymorphisms have been suggested to affect
hepatic LDL receptor activity.13 47 In addition,
cholesterol absorption has been reported to be affected by
apo E polymorphisms.48 Middle-aged subjects
who have the 2 allele absorb less cholesterol than
individuals with the most common 3 allele, while those with the
4 allele absorb more. However, these results may depend on
overall dietary cholesterol intake. Furthermore, variation
at the apo E gene locus has been suggested to influence the response to
dietary intervention.49 50 51 In a separate
analysis, we did not find any significant association
betweenfat intake and plasma lipids in the elderly regardless
of apo E genotype (Pablos-Méndez et al, unpublished
observations).
The present study is one of the first comparing the association
between apo E polymorphisms and plasma lipids in different ethnic
groups. Previously, the Framingham Offspring Study evaluated the
association between apo E phenotype and plasma lipids in 2258
Caucasian individuals 19 to 78 years old.28 Apo E
phenotype was associated with plasma LDL
cholesterol levels and apo B levels in men and women. The
average effect of the 2 allele was to lower LDL by 9.2 mg/dL in
men and by 13.7 mg/dL in women, while the average effect of the 4
allele was to increase LDL-cholesterol by 2.6 mg/dL in
men and by 5.4 mg/dL in women.28 These results
are in agreement with the pronounced effect of the apo 2 allele
in the present study in an elderly multiethnic population. While
the association between apo 2 and LDL cholesterol was
present in each of the three ethnic groups studied, the effect was
significantly lower among Hispanic elderly subjects, who had lower LDL
cholesterol levels, than in African-Americans or
non-Hispanic Caucasians (Fig 1). The reasons for the weaker association
between apo 2 and LDL cholesterol levels in Hispanics
remains to be elucidated. In contrast to the findings on LDL
cholesterol levels, we found no significant association
between apo E polymorphisms and HDL cholesterol.
However, as seen in Table 5, HDL cholesterol levels were
higher in Caucasian elderly subjects with apo 2 alleles, which
together with the effect on LDL cholesterol levels
contributed to the striking positive impact of apo 2 on the
total/HDL cholesterol ratio in this particular ethnic
group. Although it might have been desirable to analyze the
relationships between apo E genotype and serum lipid levels
separately within subgroups defined by gender and race/ethnicity,
statistical power would have been very limited within these six cells
to both detect and rule out associations, owing to relatively large
standard deviations of the lipid values, the presence of several apo E
alleles to be considered (eg, zero, one, or two E4 alleles),
and the small numbers of subjects in the cells. We therefore used a
multivariate regression procedure to adjust
simultaneously for the effects of age, sex, and
race/ethnicity on the relationships between apo E genotype and
lipid levels and to examine the modifying effects of sex and
race/ethnicity on these associations (Table 5).
The role of the apo 2 allele in CHD has been debated, and
although it has been shown to associate with lower LDL
cholesterol levels, it has frequently been associated with
hypertriglyceridemia.27
Mechanistic studies have demonstrated a significant impact of apo E
polymorphisms on postprandial triglyceride levels, the
2 allele being associated with a more prominent response to a
fat load.52 It has been argued that this
association between the apo 2 allele and
triglycerides might negate the potentially protective
effects of lower LDL cholesterol
levels.20 In the present study, however,
plasma triglyceride levels were normal, and the apo 2
allele did not significantly correlate with plasma
triglyceride levels. This suggest that the effects of the
individual apo E alleles may differ in the elderly. One possible
explanation for these findings is that dietary fat intake is lower in
the elderly, and this might suppress the influence of the 2
allele on plasma triglyceride levels. However, no
support for this hypothesis was present in our data. Even among
subjects with the highest intake of fat, no association was found.
Whatever the mechanism, our findings that the presence of the apo 2
allele resulted in lower LDL cholesterol levels and a
lower total/HDL cholesterol ratio in the absence of
hypertriglyceridemia might suggest a
protective effect of this allele in the elderly, irrespective of
race/ethnicity. Further studies are needed to address this
possibility.
In contrast to studies in younger adults, we found no independent
association between apo 4 genotype and plasma LDL
cholesterol levels in any of the ethnic groups included.
Similar findings have recently been reported for elderly Caucasians and
also in studies on middle-aged male twins.53 54
The reasons for this apparently age-related difference are unclear.
Lower fat intake in the elderly could conceivably preclude apo 4
genotype from influencing blood lipid levels. However, the
association was lacking even among individuals with relative higher fat
intake. Another possible explanation is that apo 4 carriers who,
because of additional factors, were more likely to have high LDL
cholesterol levels may have died at a younger age; elderly
apo 4 carriers, such as those in our study, could thus
represent a select subgroup of survivors who are relatively
refractory to the effect of apo 4.29 30 31 32 33 34 55
However, not only was an important effect of apo 2 still present
in this elderly population, but the apo 4 allele frequency was
similar to the one found in younger
populations13 25 26 and the effect of age on apo
allele frequencies within the age group studied was modest and
statistically insignificant. These observations argue against a major
role of age selection on the differing associations between apo 4
and LDL-cholesterol in young and elderly populations.
Longitudinal studies are necessary, however, to clarify this
hypothesis.
In conclusion, apo E polymorphisms remain an important determinant of blood lipids in the elderly, with different effects in the three ethnic groups analyzed. The apo E2 isoform is prevalent in the elderly, more so among African-Americans, and is associated with lower LDL cholesterol levels, particularly in non-Hispanic Caucasians and African-Americans. However, the interaction between apo E, plasma lipids, and atherosclerosis is complex and, as suggested by the present study, may be different depending on age and ethnic group. Further studies are therefore needed to address the impact of variation of the apo E locus on plasma lipid fractions and risk of atherosclerosis in the different ethnic groups.
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Acknowledgments |
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The study was supported by a grant from the National Institute of Aging (PO1 AGO7232) and by a grant from the National Institutes of Health, National Center for Research Resources (RR-00645). Dr Pablos-Méndez is a GCRC-funded Minority Clinical Associate Physician, and Dr Berglund is a Florence Irving Associate Professor of Medicine and an Established Scientist of the American Heart Association, New York City Affiliate. We wish to express our gratitude to Dr Henry N. Ginsberg, Director of the Irving Center for Clinical Research at Columbia University, for his advice and support. The assistance of the nursing staff and resources of the Irving Center for Clinical Research is gratefully acknowledged.
Received March 4, 1997; accepted June 23, 1997.
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