J. Lipid Res.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1194/jlr.M400114-JLR200 on July 16, 2004

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M400114-JLR200v1
45/10/1868    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Elosua, R.
Right arrow Articles by O'Donnell, C. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Elosua, R.
Right arrow Articles by O'Donnell, C. J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Journal of Lipid Research, Vol. 45, 1868-1875, October 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Association of APOE genotype with carotid atherosclerosis in men and women

: the Framingham Heart Study

Roberto Elosua*,{dagger}, Jose M. Ordovas{dagger}, L. Adrienne Cupples*,§, Caroline S. Fox§,**,{dagger}{dagger}, Joseph F. Polak§§, Philip A. Wolf§,***, Ralph A. D'Agostino, Sr.§ and Christopher J. O'Donnell1,§,{dagger}{dagger},{dagger}{dagger}{dagger}

§ National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA
{dagger}{dagger}{dagger} Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
§§ Departments of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
** Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
*** Departments of Neurology and Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA
* Department of Biostatistics, Boston University, Boston, MA
{dagger} United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA
{dagger}{dagger} National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

Published, JLR Papers in Press, July 16, 2004. DOI 10.1194/jlr.M400114-JLR200

1 To whom correspondence should be addressed. e-mail: codonnell{at}partners.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The aim of this study was to determine the association between APOE genotype and carotid atherosclerosis, defined as intimal-medial thickness (IMT) and stenosis, and to assess if other cardiovascular risk factors modify this association. A total of 1,315 men and 1,408 women from the Framingham Offspring Study underwent carotid ultrasound during examination cycle 6 and had complete data on APOE genotype. Three APOE genotype groups were defined: APOE2 (including E2/E2, E3/E2 genotypes), APOE3 (E3/E3), and APOE4 (including E4/E3, E4/E4 genotypes). Carotid IMT and the presence of carotid stenosis > 25% were determined by ultrasonography. In women, the APOE2 group was associated with lower carotid IMT (0.67 vs. 0.73 mm) and lower prevalence of stenosis (odds ratio = 0.49; 95% confidence interval = 0.30–0.81) compared with the APOE3 group. In men, APOE genotype was not associated with carotid IMT or stenosis in the whole group; however, diabetes modified the association between APOE genotype and carotid IMT (P for interaction = 0.044). Among men with diabetes, the APOE4 group was associated with a higher internal carotid artery IMT (1.22 mm) than the APOE3 group (0.90 mm) or the APOE2 group (0.84 mm).

The E2 allele was associated with lower carotid atherosclerosis in women, and the E4 allele was associated with higher internal carotid IMT in diabetic men.

Supplementary key words genetics • atherosclerosis • carotid artery • lipoprotein • apolipoprotein E genotype


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The APOE locus is one of the candidate gene regions proposed to play an important role in atherosclerosis. Apolipoprotein E (apoE) is a plasma protein that modulates the metabolism of lipoproteins. Genetic variation in the polymorphic APOE locus significantly affects plasma lipoprotein concentrations. Three common APOE alleles have been identified: APOE*E2 (E2), APOE*E3 (E3), and APOE*E4 (E4). The presence of the E4 allele is associated with increased LDL cholesterol, whereas the presence of the E2 allele is associated with decreased LDL cholesterol (1). Both E2 and E4 are also associated with increases in plasma triglycerides (2) and increased cardiovascular disease (CVD) risk (1, 3), although the E2 allele was associated with a lower CVD risk in women in the Framingham Study (1, 4).

Carotid intimal-medial thickness (IMT) and plaque measured by ultrasound are associated with prevalent CVD (5), incident myocardial infarction and stroke (6), premature parental coronary heart disease (7), and peripheral arterial disease (8). Therefore, carotid IMT is widely used as a surrogate measure of atherosclerosis burden. Data from the Framingham Heart Study (9) and other studies (10) demonstrate that there is a substantial heritable component to carotid atherosclerosis.

The association between carotid atherosclerosis and APOE genotype has been examined previously, with discordant results (11–25). The aim of the current analyses was to determine the association between APOE genotype and carotid atherosclerosis and to assess whether other CVD risk factors modify this association in the Framingham Heart Study.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The Framingham original cohort began enrollment in 1948, with the recruitment of 5,209 men and women between the ages of 30 and 62 years. Subjects included in this analysis were participants in the offspring cohort of the Framingham Heart Study, which began in 1971 with the recruitment of 5,124 men and women who were offspring and spouses of offspring of the original cohort and ranged in age from 5 to 70 years. The study design of the Framingham original and offspring studies has been described in detail (26). There were 3,532 participants in offspring study examination cycle 6 (1995–1998). A total of 3,378 (96%) of these participants underwent B-mode carotid ultrasonography; APOE genotype data were available for 2,723 participants (81%). The research protocol was approved by the Institutional Review Board of Boston University. All participants provided informed consent.

Carotid ultrasonography
Ultrasound studies were acquired and images analyzed according to a standard protocol (27, 28). Imaging was conducted using a high-resolution 7.5 MHz transducer for the common artery and a 5.0 MHz transducer for the internal carotid artery (Toshiba Medical System). Two images were obtained at the distal common carotid artery (CCA) and two in the proximal 2 cm of the internal carotid artery (ICA). A single trained sonographer made all of the measurements and was overread by one of the investigators (J.F.P.).

For each site, the maximal IMT measurements in the near and far walls were averaged. CCA and ICA IMT were defined as the mean of the maximal IMT measurements for the right and left sides. Images were gated to diastole. Data for the mean of the mean IMT measurements for CCA and ICA IMT were also calculated (9). Based upon 25 readings by two separate readers, intraclass correlation coefficients for the mean and maximum ICA and CCA IMT were 0.74, 0.74, 0.86, and 0.90, respectively.

A subjective estimate of ICA narrowing, graded as 0%, 1–24%, and 25–49%, was made by the sonographer when Doppler-derived peak systolic velocities in the ICA were <150 cm/s. ICA narrowing of hemodynamic significance (>=50%) was defined as present when peak systolic velocities in the ICA were >=150 cm/s. For these analyses, the degree of stenosis was based on the more diseased ICA. The intrareader reproducibility of carotid stenosis (>=25%) from 159 paired readings on 79 studies was comparable to that reported in other studies ({kappa} value of 0.69).

apoE genotype
Leukocyte DNA was extracted from 5–10 ml of whole blood as previously described (29). APOE genotyping was performed as described by Hixson and Vernier (30). A 244 bp sequence of the APOE gene including the two polymorphic sites was amplified by PCR in a DNA Thermal Cycler (PTC-100; MJ Research, Watertown, MA), using oligonucleotide primers F4 and F6 (30). Each reaction mixture was heated at 94°C for 2 min and followed by 35 cycles of amplification (94°C for 40 s, 62°C for 30 s, and 72°C for 1 min). The PCR products were digested with 5 units of HhaI, and the fragments separated by electrophoresis on an 8% polyacrylamide nondenaturing gel. After electrophoresis, the gel was treated with ethidium bromide for 30 min and DNA fragments were visualized by ultraviolet illumination.

To be consistent with previous publications, we defined three APOE genotype groups: a) the APOE2 group includes those subjects carrying the E2/E2 or E3/E2 genotype; b) the APOE3 group includes those carrying the E3/E3 genotype; and c) the APOE4 group includes those carrying the E4/E3 or E4/E4 genotype. Participants with the E4/E2 genotype (n = 49) were excluded from the analyses.

Other clinical variables
Data regarding the medical history and physical examination were derived from the sixth examination cycle (31). Fasting plasma glucose was measured in fresh specimens with a hexokinase reagent kit (A-gen glucose test; Abbot, South Pasadena, CA). Diabetes was defined by fasting glucose >= 126 mg/dl or use of insulin or hypoglycemic medication. Plasma total cholesterol, HDL cholesterol, and triglycerides were measured as described previously (1). LDL cholesterol concentrations were estimated with the Friedewald equation. Subjects were classified as current cigarette smokers if they reported having smoked cigarettes during the previous year. Systolic and diastolic blood pressure values were the means of two physician-obtained measurements. The use of medications to control blood pressure was recorded. Height and weight were measured with the individual dressed in an examining gown and wearing no shoes. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Obesity was defined as BMI >= 30 kg/m2.

Statistical methods
Chi-square tests to compare proportions across groups and ANOVA to compare means of continuous variables across groups were used. Analysis of covariance was used to determine the carotid IMT mean across APOE genotypes, adjusting for covariates, separately for men and women. Logistic regression analysis was conducted to determine the association between genetic variants and the presence of ICA stenosis. Familial correlations were accounted for using Proc Genmod in SAS (version 8.0). A two-tailed P < 0.05 was considered statistically significant. To determine the association between APOE genotype and carotid atherosclerosis, we first explored the APOE genotype global effect, and afterward, all of the possible differences between groups were explored adjusting for multiple comparisons by the Scheffé method.

We also performed a meta-analysis of the data reported in published studies assessing the association between APOE genotype and carotid atherosclerosis. We included those studies with a community-based sampling, using the Review Manager program (version 4.2) (32). Random and fixed models were fitted. The meta-analysis was stratified by sex.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of the sample stratified by sex are presented in Table 1. The relative frequencies of APOE alleles were 0.08, 0.80, and 0.12 for alleles E2, E3, and E4, respectively, and the frequencies were consistent with Hardy-Weinberg equilibrium. After excluding the APOE E4/E2 genotype (n = 49; 1.77%), the frequency of APOE genotypes was 0.4, 13.3, 65.4, 19.3, and 1.6% for E2/E2, E3/E2, E3/E3, E4/E3, and E4/E4, respectively. The mean carotid IMT and the prevalence of carotid stenosis were higher in men.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Sample characteristics by sex

 
In both men and women, LDL cholesterol in the APOE2 group was lower than in the APOE3 and APOE4 groups. Moreover, in men, triglycerides were higher in the APOE4 group than in the APOE2 group, whereas in women, HDL cholesterol in the APOE2 group was higher than in the APOE4 group. No other statistically significant differences were observed. These lipid differences were consistent with previously reported results in the Framingham Study (1).

We analyzed the relation between carotid IMT and carotid stenosis. The Spearman correlation coefficients between carotid stenosis (defined as 0, 1–24, 25–49, or >=50%) and CCA IMT or ICA IMT were 0.49 and 0.52 in men and 0.43 and 0.45 in women, respectively. Moreover, the covariate-adjusted ICA IMT means (SEM) in those subjects without and with carotid stenosis >= 25% were 0.74 mm (0.01) and 1.32 mm (0.04) in men and 0.63 mm (0.01) and 1.21 mm (0.05) in women, respectively.

There was no difference in the carotid IMT or in the proportion of participants with carotid stenosis across APOE genotype groups (Table 2).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Plasma lipids, carotid IMT, and carotid stenosis across APOE genotype groups in men and women

 
We examined means of the different measurements of carotid IMT across APOE groups by sex after adjustment for age, familial correlation, and other covariates (Table 3). In men, no differences were observed in CCA or ICA IMT across APOE groups. In women, the CCA and ICA IMT in the APOE2 group were lower than those of the APOE4 and APOE3 groups. This difference was statistically significant between APOE2 and APOE4 for CCA IMT and between APOE2 and APOE3 for ICA IMT. When we included plasma lipids in the statistical model, the associations were no longer statistically significant, suggesting that the effects were, at least in part, mediated through plasma lipids (Table 3, model 3).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Age-adjusted and multivariable-adjusted mean carotid IMT across APOE genotype groups in men and women

 
Adjusted odds ratios of APOE genotype groups for ICA stenosis >= 25% are shown in Table 4. In men, no statistically significant association between APOE genotype and carotid stenosis was observed. In women, the APOE2 group was associated with a lower prevalence of carotid stenosis compared with the APOE3 and APOE4 groups. This association remained statistically significant after adjusting for lipid levels. The interaction between APOE2 and sex was statistically significant (P = 0.007). The same analyses were performed using a cutoff point of 50% for carotid stenosis; odds ratios were of similar magnitude with wider confidence intervals (data not shown).


View this table:
[in this window]
[in a new window]
  		TABLE 4. Age-adjusted and multivariable-adjusted odds ratios for carotid stenosis (>=25%) by APOE genotype in men and women

 
A statistically significant modifying effect of diabetes was noted in the association between APOE genotype and ICA IMT in men (P = 0.044) but not in women. The ICA IMT across APOE groups in men stratified by diabetes is presented in Fig. 1 . No differences across groups were observed in nondiabetic men. However, in diabetic men, the ICA IMT of the APOE4 group was statistically significantly higher than that of the APOE3 and APOE2 groups (Fig. 1). After adjusting for lipids, the interaction was marginally not statistically significant (P = 0.079), although the ICA IMT of the APOE4 group (1.18 mm) was still significantly higher than that of the APOE3 group (0.89 mm) (P = 0.049). Diabetes was associated with higher IMT only in APOE4 men (P = 0.011), whereas in women, the association between diabetes and carotid IMT was significant (P = 0.009) independently of the APOE genotype.



View larger version (28K):
[in this window]
[in a new window]
  		Fig. 1. Multivariate adjusted (age, familial correlation, systolic blood pressure, hypertension treatment, smoking, and body mass index) mean internal carotid artery (ICA) intimal medial thickness across APOE genotype groups in diabetic and nondiabetic men. The P value for the diabetes-APOE genotype interaction in ICA intimal medial thickness = 0.044.

 
There was no evidence for a significant interaction of smoking, hypertension, or obesity on the association between APOE genotype and either carotid IMT or stenosis. For all of the above analyses, we observed similar results when we used the mean of the mean IMT instead of the mean of the maximum IMT.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this community-based study, we observed that associations between APOE genotype and carotid atherosclerosis measures are modified by diabetes and by sex. In women, the E2 allele was associated with lower CCA and ICA IMT and lower prevalence of carotid stenosis. The association with IMT was mainly mediated through plasma lipids, but the association with ICA stenosis was still significant even after adjusting for lipid levels. The E4 allele was associated with higher ICA IMT in diabetic men.

The inverse association between the E2 allele and carotid atherosclerosis measures observed in women is consistent with previous research in the Framingham Heart Study showing a protective association between the E2 allele and prevalent CVD in women (1). We performed a meta-analysis to assess the consistency of our results with previously published data. In the meta-analysis of data from women, there was no significant overall association between APOE genotype and carotid atherosclerosis determined as either the continuous measure of CCA IMT or a dichotomous variable (Fig. 2 , Table 5).



View larger version (28K):
[in this window]
[in a new window]
  		Fig. 2. Common carotid artery intimal medial thickness weighted mean difference between APOE genotype groups (APOE2 and APOE4 vs. APOE3) in men and women. Meta-analysis results using random effect models.

 

View this table:
[in this window]
[in a new window]
  		TABLE 5. APOE2 and APOE4 odds ratios and their 95% CIs for carotid atherosclerosis in different studies (the APOE3 group is the reference group), and overall association estimated by meta-analysis using random effects models, excluding (Overall-a) and including (Overall-b) the results of this study

 
In men, we observed a direct but nonsignificant association between the E2 allele and carotid stenosis. The E2 allele was not significantly associated with carotid IMT, although it tended to be associated with higher ICA IMT and with lower CCA IMT. In the meta-analysis for men, there was an inverse and significant association between the E2 allele and CCA IMT (Fig. 2) and a direct and nonsignificant association between the E2 allele and carotid atherosclerosis as a dichotomous variable (Table 5). These paradoxical results are consistent with previous observations that APOE genotype (24) and classic risk factors (33) are associated with a segment-specific carotid IMT and support the hypothesis that different pathophysiologic mechanisms may explain the observed differences between ICA and CCA. Turbulent blood flow in regions of arterial bifurcation, such as the ICA, may predispose to lipid deposition and thrombosis (34). Laminar blood flow, as seen in the CCA, is mainly related to wall shear stress. If the wall shear stress decreases, the time that blood comes in contact with endothelial cells increases and may enhance the delivery of atherogenic particles to the arterial wall (35). These different mechanisms may underlie the observed disparity in the associations between APOE genotype and CCA and ICA IMT.

The modifying effect of sex on the association between APOE2 and carotid atherosclerosis is not well understood, although some plausible explanations exist. Carriers of the E2 allele present a higher concentration of atherogenic triglyceride-rich lipoprotein (TRL) (36). In men, the atherogenic potential associated with TRL may be expressed in subjects with lower HDL cholesterol, whereas in women, this atherogenic effect may be counterbalanced by their higher HDL cholesterol levels. The higher postprandial TRL response present in men compared with women (37) may also play a role in this sex difference. Additionally, estrogens upregulate APOE gene expression, resulting in higher apoE production and a more efficient remnant clearance (38).

We did not observe a significant association between the E4 allele and carotid atherosclerosis. The association between the E4 allele and higher carotid IMT has been observed in several studies (13, 22–24), although others have failed to find such an association (11, 15–22). In the meta-analysis, the E4 allele was not associated with either carotid IMT or carotid atherosclerosis (Fig. 2B–D, Table 5).

In our study, although it was associated with a nonsignificant increase in ICA IMT in men, the E4 allele was significantly associated with higher carotid IMT only in diabetic men. This observation has been previously reported (39) and suggested in patients with peripheral arterial disease (40), for exercise-induced silent myocardial ischemia (41), and for cognitive decline (42). The combination of the E4 allele and diabetes could increase the concentration of small, dense LDLs and inflammatory biomarkers, thereby increasing the risk of carotid atherosclerosis. We have recently documented in the same population an interaction between APOE genotype and obesity on fasting insulin and glucose levels in men (43). Taken together, these data suggest that the E4 allele risk may be much higher in men with the metabolic syndrome.

Although we examined a priori for plausible interactions, it is possible that our observed interaction is falsely positive, given the multiple comparisons examined during our analyses.

There are several potential explanations for the differences in the presence and magnitude of associations between APOE genotype and carotid atherosclerosis measurements across studies (44). Differences in the study population characteristics, methods of carotid atherosclerosis measurement (CCA or ICA IMT, carotid plaque, carotid stenosis), statistical analyses (sex stratification, interaction terms analyzed), and small sample sizes and differing prevalences of diabetes may contribute to the reported variability. Diet (45) and exercise (46) also modify the association between APOE genotype and plasma lipid levels. Our study is conducted in men and women from a community-based cohort with a typical distribution of risk factor profiles and prevalence of diabetes. Differences with other populations in these environmental factors may explain some of the observed variation.

Some limitations of our study exist. Misclassification bias may have occurred in the subjective evaluation of carotid stenosis, although we consider that this misclassification would be random and lead to a conservative bias.

Conclusion
APOE2 genotype was associated with lower carotid atherosclerosis in women, supporting the previous observation of the protective role of this genotype on CVD only in women (1). The mechanisms of this sex interaction remain to be determined. APOE4 genotype was significantly associated with a higher ICA IMT only in diabetic men. Although this observation should be considered with caution, the different association between APOE genotype and atherosclerosis in diabetic and nondiabetic patients could have prognostic and therapeutic implications.


   ACKNOWLEDGMENTS
 
This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195), by the National Institute of Neurological Disorders and Stroke (5R01-NS17950-22), and by National Institutes of Health/National Heart, Lung, and Blood Institute Grant HL-54776 and contracts 53-K06-5-10 and 58-1950-9-001 from the U.S. Department of Agriculture Agricultural Research Service. R.E. received a grant from the Fulbright-Generalitat de Catalonia Program.

Manuscript received March 22, 2004 and in revised form June 28, 2004. and in re-revised form July 2, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
  1. Wilson, P. W. F., R. H. Myers, M. G. Larson, J. M. Ordovas, P. A. Wolf, and E. J. Schaefer. 1994. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study. J. Am. Med. Assoc. 272: 1666–1671.[Abstract]

  2. Dallongeville, J., S. Lussier-Cacan, and J. Davignon. 1992. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis. J. Lipid Res. 33: 447–454.[Abstract]

  3. Wilson, P. W. F., E. J. Schaefer, M. G. Larson, and J. M. Ordovas. 1996. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler. Thromb. Vasc. Biol. 16: 1250–1255.[Abstract/Free Full Text]

  4. Lahoz, C., E. J. Schaefer, L. A. Cupples, P. W. F. Wilson, D. Levy, D. Osgood, S. Parpos, J. Pedro-Botet, J. A. Daly, and J. M. Ordovas. 2001. Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis. 154: 529–537.[CrossRef][Medline]

  5. Burke, G. L., G. W. Evans, W. A. Riley, A. R. Sharrett, G. Howard, R. W. Barnes, W. Rosamond, R. S. Crow, P. M. Rautaharju, and G. Heiss. 1995. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) study. Stroke. 26: 386–391.[Abstract/Free Full Text]

  6. O'Leary, D. H., J. F. Polak, R. A. Kronmal, T. A. Manolio, G. L. Burke, and S. K. Wolfson, Jr. 1999. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N. Engl. J. Med. 340: 14–22.[Abstract/Free Full Text]

  7. Wang, T. J., B. H. Nam, R. B. D'Agostino, P. A. Wolf, D. M. Lloyd-Jones, C. A. MacRae, P. W. Wilson, J. F. Polak, and C. J. O'Donnell. 2003. Carotid intima-media thickness is associated with premature parental coronary heart disease. The Framingham Heart Study. Circulation. 108: 572–576.[Abstract/Free Full Text]

  8. Allan, P. L., P. I. Mowbray, A. J. Lee, and F. G. Fowkes. 1997. Relationship between carotid intima-media thickness and symptomatic and asymptomatic peripheral arterial disease. The Edinburgh Artery Study. Stroke. 28: 348–353.[Abstract/Free Full Text]

  9. Fox, C. S., J. F. Polak, I. Chazaro, A. Cupples, P. A. Wolf, R. A. D'Agostino, and C. J. O'Donnell. 2003. Genetic and environmental contributions to atherosclerosis phenotypes in men and women: heritability of carotid intima-media thickness in the Framingham Heart Study. Stroke. 34: 397–401.[Abstract/Free Full Text]

  10. Hunt, K. J., R. Duggirala, H. H. Goring, J. T. Williams, L. Almasy, J. Blangero, D. H. O'Leary, and M. P. Stern. 2002. Genetic basis of variation in carotid artery plaque in the San Antonio Family Heart Study. Stroke. 33: 2775–2780.[Abstract/Free Full Text]

  11. Beilby, J. P., C. C. Hunt, L. J. Palmer, C. M. Chapman, J. P. Burley, B. M. McQuillan, P. L. Thompson, and J. Hung. 2003. Apolipoprotein E gene polymorphisms are associated with carotid plaque formation but not with intima-media wall thickness: results from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Stroke. 34: 869–874.[Abstract/Free Full Text]

  12. Karvonen, J., H. Kauma, K. Kervinen, O. Ukkola, M. Rantala, M. Paivansalo, M. J. Savolainen, and Y. A. Kesaniemi. 2002. Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men. J. Hypertens. 20: 2371–2378.[CrossRef][Medline]

  13. Haraki, T., T. Takegoshi, C. Kitoh, T. Wakasugi, T. Saga, J. I. Hirai, T. Aayama, A. Inazu, and H. Mabuchi. 2002. Carotid artery intima-media thickness and brachial artery flow-mediated vasodilation in asymptomatic Japanese male subjects amongst apolipoprotein E phenotypes. J. Intern. Med. 252: 114–120.[CrossRef][Medline]

  14. Djousse, L., R. H. Myers, M. A. Province, S. C. Hunt, J. H. Eckfeldt, G. Evans, J. M. Peacock, and R. C. Ellison. 2002. Influence of apolipoprotein E, smoking, and alcohol intake on carotid atherosclerosis. National Heart, Lung, and Blood Institute Family Heart Study. Stroke. 33: 1357–1361.[Abstract/Free Full Text]

  15. Slooter, A. J., M. L. Bots, L. M. Havekes, A. I. del Sol, M. Cruts, D. E. Grobbee, A. Hofman, C. Van Broeckhoven, J. C. Witteman, and C. M. van Duijn. 2001. Apolipoprotein E and carotid artery atherosclerosis. The Rotterdam Study. Stroke. 32: 1947–1952.[Abstract/Free Full Text]

  16. Ilveskoski, E., A. Loimaala, M. F. Mercury, T. Lehtimaki, M. Pasanen, A. Nenonen, P. Oja, M. G. Bond, T. Koivula, P. J. Karhunen, and I. Vuori. 2000. Apolipoprotein E polymorphism and carotid intima media thickness in a random sample of middle-aged men. Atherosclerosis. 153: 147–153.[CrossRef][Medline]

  17. Horejsi, B., J. Spacil, R. Ceska, M. Vrablik, T. Haas, and A. Horinek. 2000. The independent correlation of the impact of lipoprotein(a) levels and apolipoprotein E polymorphism on carotid artery intima thickness. Int. Angiol. 19: 331–336.[Medline]

  18. Hanon, O., X. Girerd, V. Luong, X. Jeunemaitre, S. Laurent, and M. E. Safar. 2000. Association between the apolipoprotein E polymorphism and arterial wall thickness in asymptomatic adults. J. Hypertens. 18: 431–436.[CrossRef][Medline]

  19. Zannad, F., S. Visvikis, R. Gueguen, R. Sass, O. Chapet, B. Herbeth, and G. Siest. 1998. Genetics strongly determines the wall thickness of the left and right carotid arteries. Hum. Genet. 103: 183–188.[CrossRef][Medline]

  20. Sass, C., F. Zannad, B. Herbeth, D. Salah, O. Chapet, G. Siest, and S. Visvikis. 1998. Apolipoprotein E4, lipoprotein lipase C447 and angiotensin-I converting enzyme deletion alleles were not associated with increased wall thickness of carotid and femoral arteries in healthy subjects from the Stanislas cohort. Atherosclerosis. 140: 89–95.[CrossRef][Medline]

  21. Kogawa, K., Y. Nishizawa, M. Hosoi, T. Kawagishi, K. Maekawa, T. Shoji, Y. Okumo, and H. Morii. 1997. Effect of polymorphism of apolipoprotein E and angiotensin-converting enzyme genes on arterial wall thickness. Diabetes. 46: 682–687.[Abstract]

  22. Vauhkonen, I., L. Niskanen, M. Ryynanen, R. Voutilainen, J. Partanen, J. Toyry, M. Mercuri, R. Rauramaa, and M. Uusitupa. 1997. Divergent association of apolipoprotein E polymorphism with vascular disease in patients with NIDDM and control subjects. Diabetes Med. 14: 748–756.[CrossRef][Medline]

  23. Cattin, L., M. Fisicaro, M. Tonizzo, M. Valenti, G. M. Danek, M. Fonda, P. G. Da Col, S. Casagrande, E. Pincetri, M. Bovenzi, and F. Baralle. 1997. Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults. Arterioscler. Thromb. Vasc. Biol. 17: 91–94.[Abstract/Free Full Text]

  24. Terry, J. G., G. Howard, M. Mercuri, M. G. Bond, and J. R. Crouse 3rd. 1996. Apolipoprotein E polymorphism is associated with segment-specific extracranial carotid artery intima-media thickening. Stroke. 27: 1755–1759.[Abstract/Free Full Text]

  25. De Andrade, M., I. Thandi, S. Brown, A. Gotto, Jr., W. Patsch, and E. Boerwinkle. 1995. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am. J. Hum. Genet. 56: 1379–1390.[Medline]

  26. Kannel, W. B., M. Feinleib, P. M. McNamara, R. J. Garrison, and W. P. Castelli. 1979. An investigation of coronary heart disease in families. The Framingham Offspring Study. Am. J. Epidemiol. 110: 281–290.[Abstract/Free Full Text]

  27. Polak, J. F., D. H. O'Leary, R. A. Kronmal, S. K. Wolfson, M. G. Bond, R. P. Tracy, J. M. Gardin, S. J. Kittner, T. R. Price, and P. J. Savage. 1993. Sonographic evaluation of carotid artery atherosclerosis in the elderly: relationship of disease severity to stroke and transient ischemic attack. Radiology. 188: 363–370.[Abstract/Free Full Text]

  28. O'Leary, D. H., J. F. Polak, R. A. Kronmal, S. J. Kittner, M. G. Bond, S. K. Wolfson, Jr., W. Bommer, T. R. Price, J. M. Gardin, and P. J. Savage. 1992. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke. 23: 1752–1760.[Abstract/Free Full Text]

  29. Miller, S. A., D. D. Dykes, and H. F. Polesky. 1988. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16: 1215.[Free Full Text]

  30. Hixson, J. E., and D. T. Vernier. 1990. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J. Lipid Res. 31: 545–548.[Abstract]

  31. Cupples, L. A., R. B. D'Agostino, and D. Kiely. 1988. The Framingham Heart Study, Section 35. An Epidemiological Investigation of Cardiovascular Disease. Survival Following Cardiovascular Events: 30 Year Follow-Up. National Heart, Lung, and Blood Institute, Bethesda, MD.

  32. Review Manager (RevMan) Ver. 4.2 for Windows. The Cochrane Collaboration, Oxford, England.

  33. Espeland, M. A., R. Tang, J. G. Terry, D. H. Davis, M. Mercuri, and J. R. Crouse 3rd. 1999. Associations of risk factors with segment-specific intimal-medial thickness of the extracranial carotid artery. Stroke. 30: 1047–1055.[Abstract/Free Full Text]

  34. Grabowski, E. F., and F. P. Lam. 1995. Endothelial cell function, including tissue factor expression, under flow conditions. Thromb. Haemost. 74: 123–128.[Medline]

  35. Gnasso, A., C. Carallo, C. Irace, V. Spagnuolo, G. De Novara, P. L. Mattioli, and A. Pujia. 1996. Association between intima-media thickness and wall shear stress in common carotid arteries in healthy male subjects. Circulation. 94: 3257–3262.[Abstract/Free Full Text]

  36. Dallongeville, J., L. Tiret, S. Visvikis, D. S. O'Reilly, M. Saava, G. Tsitouris, M. Rosseneu, G. DeBacker, S. E. Humphries, and U. Beisiegel. 1999. Effect of apo E phenotype on plasma postprandial triglyceride levels in young male adults with and without a familial history of myocardial infarction. The EARS II Study. European Atherosclerosis Research Study. Atherosclerosis. 145: 381–388.[CrossRef][Medline]

  37. Couillard, C., N. Bergeron, D. Prud'homme, J. Bergeron, A. Tremblay, C. Bouchard, P. Mauriège, and J. P. Després. 1999. Gender differences in postprandial lipemia. Importance of visceral adipose tissue accumulation. Arterioscler. Thromb. Vasc. Biol. 19: 2448–2455.[Abstract/Free Full Text]

  38. Srivastava, R. A., N. Srivastava, M. Averna, R. C. Lin, K. S. Korach, D. B. Lubahn, and G. Schonfeld. 1997. Estrogen up-regulates apolipoprotein E (ApoE) gene expression by increasing ApoE mRNA in the translating pool via the estrogen receptor alpha-mediated pathway. J. Biol. Chem. 272: 33360–33366.[Abstract/Free Full Text]

  39. Xiang, G., T. Hu, and Y. Wang. 2003. Apolipoprotein E genotype and carotid atherosclerosis in type 2 diabetes mellitus (In Chinese). Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 20: 66–68.[Medline]

  40. Resnik, H. E., B. Rodriguez, R. Havlik, L. Ferrucci, D. Foley, J. D. Curb, and T. B. Harris. 2000. Apo E genotype, diabetes, and peripheral arterial disease in older men. The Honolulu-Asia Aging Study. Genet. Epidemiol. 19: 52–63.[CrossRef][Medline]

  41. Guangda, X., X. Bangshun, L. Xiujian, and H. Yangzhong. 1999. Apovarepsilon (4) allele increases the risk for exercise-induced silent myocardial ischemia in non-insulin-dependent diabetes mellitus. Atherosclerosis. 147: 293–296.[CrossRef][Medline]

  42. Haan, M. N., L. Shemanski, W. J. Jagust, T. A. Manolio, and L. Kuller. 1999. The role of APOE epsilon 4 in modulating effects of other risk factors for cognitive decline in elderly persons. J. Am. Med. Assoc. 282: 40–46.[Abstract/Free Full Text]

  43. Elosua, R., S. Demissie, L. A. Cupples, J. B. Meigs, P. W. F. Wilson, E. J. Schaefer, D. Corella, and J. M. Ordovas. 2003. Obesity modulates the association among APOE genotype, insulin, and glucose in men. Obes. Res. 11: 1502–1508.[Medline]

  44. Colhoun, H. M., P. M. McKeigue, and G. D. Smith. 2003. Problems of reporting genetic associations with complex outcomes. Lancet. 361: 865–872.[CrossRef][Medline]

  45. Ordovas, J. M., and E. J. Schaeffer. 1999. Genes, variation of cholesterol and fat intake and serum lipids. Curr. Opin. Lipidol. 10: 15–22.[CrossRef][Medline]

  46. Bernstein, M. S., M. C. Costanza, R. W. James, M. A. Morris, F. Cambien, S. Raoux, and A. Morabia. 2002. Physical activity may modulate effects of ApoE genotype on lipid profile. Arterioscler. Thromb. Vasc. Biol. 22: 133–140.[Abstract/Free Full Text]


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Lipid Res.Home page
D. C. Crawford, A. S. Nord, M. D. Badzioch, J. Ranchalis, L. A. McKinstry, M. Ahearn, C. Bertucci, C. Shephard, M. Wong, M. J. Rieder, et al.
A common VLDLR polymorphism interacts with APOE genotype in the prediction of carotid artery disease risk
J. Lipid Res., March 1, 2008; 49(3): 588 - 596.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
L. Paternoster, N. A. Martinez Gonzalez, S. Lewis, and C. Sudlow
Association Between Apolipoprotein E Genotype and Carotid Intima-Media Thickness May Suggest a Specific Effect on Large Artery Atherothrombotic Stroke
Stroke, January 1, 2008; 39(1): 48 - 54.
[Abstract] [Full Text] [PDF]

Home page
 Am J EpidemiolHome page
K. A. Volcik, R. A. Barkley, R. G. Hutchinson, T. H. Mosley, G. Heiss, A. R. Sharrett, C. M. Ballantyne, and E. Boerwinkle
Apolipoprotein E Polymorphisms Predict Low Density Lipoprotein Cholesterol Levels and Carotid Artery Wall Thickness but Not Incident Coronary Heart Disease in 12,491 ARIC Study Participants
Am. J. Epidemiol., August 15, 2006; 164(4): 342 - 348.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
L. E. Viiri, O. T. Raitakari, H. Huhtala, M. Kahonen, R. Rontu, M. Juonala, N. Hutri-Kahonen, J. Marniemi, J. S. A. Viikari, P. J. Karhunen, et al.
Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults
J. Lipid Res., June 1, 2006; 47(6): 1298 - 1306.
[Abstract] [Full Text] [PDF]

Home page
 Alcohol AlcoholHome page
M. BEDNARSKA-MAKARUK, M. RODO, C. MARKUSZEWSKI, A. ROZENFELD, M. SWIDERSKA, B. HABRAT, and H. WEHR
POLYMORPHISMS OF APOLIPOPROTEIN E AND ANGIOTENSIN-CONVERTING ENZYME GENES AND CAROTID ATHEROSCLEROSIS IN HEAVY DRINKERS
Alcohol Alcohol., July 1, 2005; 40(4): 274 - 282.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M400114-JLR200v1
45/10/1868    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Elosua, R.
Right arrow Articles by O'Donnell, C. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Elosua, R.
Right arrow Articles by O'Donnell, C. J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today