This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Social Bookmarking   What's this?

The Framingham Offspring Study

Peter W. F. Wilson, MD; Richard H. Myers, PhD; Martin G. Larson, ScD; Jose M. Ordovas, PhD; Philip A. Wolf, MD; Ernst J. Schaefer, MD

JAMA. 1994;272(21):1666-1671.

Abstract
Objective.
—To describe the association between apolipoprotein E alleles (2, 3, and 4), dyslipidemias, and coronary heart disease (CHD).

Design.
—Cross-sectional prevalence study.

Setting and Participants.
—Community-based sample of men (n=1034) and women (n=916) aged 40 to 77 years who are participating in a long-term study of cardiovascular disease. Study participants underwent fasting lipid measurements, coronary risk factor determinations, and a comprehensive evaluation for the presence of current or previous CHD.

Results.
—Compared with the 3 allele, the 4 allele was associated with elevated low-density lipoprotein cholesterol values (4.14 mmol/L [160 mg/dL]) in women, the 2 and 4 alleles were associated with moderately elevated triglyceride values (2.82 mmol/L [250 mg/dL]) in men, and the 2 allele was associated with severely elevated triglyceride values (5.64 mmol/L [500 mg/dL]) in men. The apolipoprotein E alleles were not associated with hypertension, obesity, smoking, or diabetes, but the 4 allele frequency was reduced in women after 60 years of age. The age-adjusted prevalence of CHD was associated with the 4 allele in both men (relative odds=1.53, P=.04) and women (relative odds=1.99, P=.05). In analyses for women and for both sexes combined, this relation persisted after adjustment by hypertension, smoking, obesity, diabetes, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.

Conclusions.
—Apolipoprotein E alleles are important genetic markers for dyslipidemia and CHD. The estimated CHD odds associated with the 4 allele appears to be greater than that for any other known genetic lipid abnormality, and the association of the 4 allele with CHD remains significant in women and both sexes combined after adjustment by traditional coronary risk factors and lipids.

(JAMA. 1994;272:1666-1671)

Author Affiliations
From the Framingham (Mass) Heart Study (Drs Wilson and Larson); Boston (Mass) University Medical Center (Drs Myers and Wolf); and the US Department of Agriculture Human Nutrition Center on Aging, Tufts University, Boston, Mass (Drs Ordovas and Schaefer).

Footnotes
Reprint requests to Framingham Heart Study, 5 Thurber St, Framingham, MA 01701 (Dr Wilson).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

APOE Genotype, Lipids, and Coronary Heart Disease Risk: A Prospective Population Study
Ward et al.
Arch Intern Med 2009;169:1424-1429.
ABSTRACT | FULL TEXT  

Distinct patterns of brain activity in young carriers of the APOE-{varepsilon}4 allele
Filippini et al.
Proc. Natl. Acad. Sci. USA 2009;106:7209-7214.
ABSTRACT | FULL TEXT  

Apolipoprotein E Gene Polymorphism and Gender
Kolovou et al.
Annals of Clinical & Laboratory Science 2009;39:120-133.
ABSTRACT | FULL TEXT  

Apolipoprotein E Gene Polymorphism and Obesity Status in Middle-aged Men with Coronary Heart Disease
KOLOVOU et al.
In Vivo 2009;23:33-39.
ABSTRACT | FULL TEXT  

Serum Lipid and Antioxidant Responses in Hypercholesterolemic Men and Women Receiving Plant Sterol Esters Vary by Apolipoprotein E Genotype
Sanchez-Muniz et al.
J. Nutr. 2009;139:13-19.
ABSTRACT | FULL TEXT  

Genetic and Genomic Discovery Using Family Studies
Borecki and Province
Circulation 2008;118:1057-1063.
FULL TEXT  

CETP Genes, Metabolic Effects, and Coronary Disease Risk
Wilson
JAMA 2008;299:2795-2796.
FULL TEXT  

Apolipoprotein E3- and Nitric Oxide-Dependent Modulation of Endothelial Cell Inflammatory Responses
Mullick et al.
Arterioscler. Thromb. Vasc. Bio. 2007;27:339-345.
ABSTRACT | FULL TEXT  

Apolipoprotein E Genotype and Circulating Interleukin-10 Levels in Patients With Stable and Unstable Coronary Artery Disease
Tziakas et al.
J Am Coll Cardiol 2006;48:2471-2481.
ABSTRACT | FULL TEXT  

Lower Prevalence of Epsilon 4 Allele of Apolipoprotein E Gene in Healthy, Longer-Lived Individuals of Hellenic Origin
Stakias et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2006;61:1228-1231.
ABSTRACT | FULL TEXT  

APOE4-VLDL Inhibits the HDL-Activated Phosphatidylinositol 3-Kinase/Akt Pathway via the Phosphoinositol Phosphatase SHIP2
DeKroon et al.
Circ. Res. 2006;99:829-836.
ABSTRACT | FULL TEXT  

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
Volcik et al.
Am J Epidemiol 2006;164:342-348.
ABSTRACT | FULL TEXT  

Genetic Variation of the Renin-Angiotensin System and Chronic Kidney Disease Progression in Black Individuals in the Atherosclerosis Risk in Communities Study
Hsu et al.
J. Am. Soc. Nephrol. 2006;17:504-512.
ABSTRACT | FULL TEXT  

Polymorphisms in the PON gene cluster are associated with Alzheimer disease
Erlich et al.
Hum Mol Genet 2006;15:77-85.
ABSTRACT | FULL TEXT  

Apolipoprotein E Genotype in Matched Men and Women with Coronary Heart Disease
Kolovou et al.
Annals of Clinical & Laboratory Science 2005;35:391-396.
ABSTRACT | FULL TEXT  

apoE4 allele and the natural history of cardiovascular risk factors
Scuteri et al.
Am. J. Physiol. Endocrinol. Metab. 2005;289:E322-E327.
ABSTRACT | FULL TEXT  

Apolipoprotein E and Progression of Chronic Kidney Disease
Hsu et al.
JAMA 2005;293:2892-2899.
ABSTRACT | FULL TEXT  

The Apolipoprotein E {epsilon}4 Allele Increases the Odds of Chronic Cerebral Infarction Detected at Autopsy in Older Persons
Schneider et al.
Stroke 2005;36:954-959.
ABSTRACT | FULL TEXT  

Influence of apolipoprotein E genotype on fat-soluble plasma antioxidants in Spanish children
Ortega et al.
Am. J. Clin. Nutr. 2005;81:624-632.
ABSTRACT | FULL TEXT  

Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins E3, E2 (Arg158->Cys), and E3-Leiden
Lee et al.
J. Lipid Res. 2004;45:2199-2210.
ABSTRACT | FULL TEXT  

Stroke risk profile, brain volume, and cognitive function: The Framingham Offspring Study
Seshadri et al.
Neurology 2004;63:1591-1599.
ABSTRACT | FULL TEXT  

Association of APOE genotype with carotid atherosclerosis in men and women: the Framingham Heart Study
Elosua et al.
J. Lipid Res. 2004;45:1868-1875.
ABSTRACT | FULL TEXT  

The Effect of Dietary Fat on LDL Size Is Influenced by Apolipoprotein E Genotype in Healthy Subjects
Moreno et al.
J. Nutr. 2004;134:2517-2522.
ABSTRACT | FULL TEXT  

Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification
Doherty et al.
Endocr. Rev. 2004;25:629-672.
ABSTRACT | FULL TEXT  

Preliminary report on the interaction of apolipoprotein E polymorphism with aortic atherosclerosis and acute nephropathy after CABG
MacKensen et al.
Ann. Thorac. Surg. 2004;78:520-526.
ABSTRACT | FULL TEXT  

Modest Protective Effects of Isoflavones from a Red Clover-Derived Dietary Supplement on Cardiovascular Disease Risk Factors in Perimenopausal Women, and Evidence of an Interaction with ApoE Genotype in 49-65 Year-Old Women
Atkinson et al.
J. Nutr. 2004;134:1759-1764.
ABSTRACT | FULL TEXT  

Mendelian randomization: prospects, potentials, and limitations
Smith and Ebrahim
Int J Epidemiol 2004;33:30-42.
FULL TEXT  

Genetic Determinants of Arterial Calcification Associated With Atherosclerosis
Doherty et al.
Mayo Clin Proc. 2004;79:197-210.
ABSTRACT  

The APOE Gene and Differences in Life Expectancy in Europe
Ewbank
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2004;59:B16-20.
ABSTRACT | FULL TEXT  

Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors
Hirashiki et al.
J Am Coll Cardiol 2003;42:1429-1437.
ABSTRACT | FULL TEXT  

Distributions of ACE and APOE Polymorphisms and Their Relations With Dementia Status in Korean Centenarians
Choi et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2003;58:M227-231.
ABSTRACT | FULL TEXT  

Isoform-Dependent Cholesterol Efflux From Macrophages by Apolipoprotein E Is Modulated by Cell Surface Proteoglycans
Hara et al.
Arterioscler. Thromb. Vasc. Bio. 2003;23:269-274.
ABSTRACT | FULL TEXT  

The Epsilon 2 and 4 Alleles of Apolipoprotein E and Ischemic Vascular Events in the Greek Population -- Implications for the Interpretation of Similar Studies
Kolovou et al.
ANGIOLOGY 2003;54:51-58.
ABSTRACT  

Apolipoprotein E Polymorphism and Atherosclerosis
Kolovou et al.
ANGIOLOGY 2003;54:59-71.
ABSTRACT  

Homocysteine and Coronary Heart Disease: How Great Is the Hazard?
Wilson
JAMA 2002;288:2042-2043.
FULL TEXT  

Influence of apoE domain structure and polymorphism on the kinetics of phospholipid vesicle solubilization
Segall et al.
J. Lipid Res. 2002;43:1688-1700.
ABSTRACT | FULL TEXT  

Association Between Apolipoprotein E Genotype and Alzheimer Disease in African American Subjects
Graff-Radford et al.
Arch Neurol 2002;59:594-600.
ABSTRACT | FULL TEXT  

Lipoproteins, nutrition, and heart disease
Schaefer
Am. J. Clin. Nutr. 2002;75:191-212.
ABSTRACT | FULL TEXT  

Alcohol drinking determines the effect of the APOE locus on LDL-cholesterol concentrations in men: the Framingham Offspring Study
Corella et al.
Am. J. Clin. Nutr. 2001;73:736-745.
ABSTRACT | FULL TEXT  

Apolipoprotein E Polymorphisms and Age at First Coronary Artery Bypass Graft
Newman et al.
Anesth. Analg. 2001;92:824-829.
ABSTRACT | FULL TEXT  

Apolipoprotein E genotype and coronary heart disease
Batalla et al.
J Am Coll Cardiol 2001;37:329-330.
FULL TEXT  

Synergistic Effect between Apolipoprotein E and Angiotensinogen Gene Polymorphisms in the Risk for Early Myocardial Infarction
Batalla et al.
Clin. Chem. 2000;46:1910-1915.
ABSTRACT | FULL TEXT  

Cognitive Performance in Hypertensive and Normotensive Older Subjects
Harrington et al.
Hypertension 2000;36:1079-1082.
ABSTRACT | FULL TEXT  

Apolipoprotein E genotypes and response of plasma lipids and progression-regression of coronary atherosclerosis to lipid-lowering drug therapy
Ballantyne et al.
J Am Coll Cardiol 2000;36:1572-1578.
ABSTRACT | FULL TEXT  

Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype
Frikke-Schmidt et al.
J. Lipid Res. 2000;41:1812-1822.
ABSTRACT | FULL TEXT  

Rapid westernization of children's blood cholesterol in 3 countries: evidence for nutrient-gene interactions?
Couch et al.
Am. J. Clin. Nutr. 2000;72 :1266S-1274S.
ABSTRACT | FULL TEXT  

Small Concomitant Vascular Lesions Do Not Influence Rates of Cognitive Decline in Patients With Alzheimer Disease
Lee et al.
Arch Neurol 2000;57:1474-1479.
ABSTRACT | FULL TEXT  

Apolipoprotein epsilon 2 Allele Is Associated With an Anti-atherogenic Lipoprotein Profile in Children: The Columbia University BioMarkers Study
Isasi et al.
Pediatrics 2000;106:568-575.
ABSTRACT | FULL TEXT  

ApoE Polymorphism and Fish Oil Supplementation in Subjects With an Atherogenic Lipoprotein Phenotype
Minihane et al.
Arterioscler. Thromb. Vasc. Bio. 2000;20:1990-1997.
ABSTRACT | FULL TEXT  

Association Between Severe Cerebral Amyloid Angiopathy and Cerebrovascular Lesions in Alzheimer Disease Is Not a Spurious One Attributable to Apolipoprotein E4
Olichney et al.
Arch Neurol 2000;57:869-874.
ABSTRACT | FULL TEXT  

Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy
Tarnow et al.
Nephrol Dial Transplant 2000;15:625-630.
ABSTRACT | FULL TEXT  

Apolipoprotein E Genotype and the Risk of Recurrent Lobar Intracerebral Hemorrhage
O'Donnell et al.
NEJM 2000;342:240-245.
ABSTRACT | FULL TEXT  

The association between APOE and dementia does not seem to be mediated by vascular factors
Prince et al.
Neurology 2000;54:397-397.
ABSTRACT | FULL TEXT  

Effect of Macrophage-Derived Mouse ApoE, Human ApoE3-Leiden, and Human ApoE2 (Arg158->Cys) on Cholesterol Levels and Atherosclerosis in ApoE-Deficient Mice
Van Eck et al.
Arterioscler. Thromb. Vasc. Bio. 2000;20:119-127.
ABSTRACT | FULL TEXT  

APOE genotype as a risk factor for ischemic cerebrovascular disease: A meta-analysis
McCarron et al.
Neurology 1999;53:1308-1308.
ABSTRACT | FULL TEXT  

Association between apolipoprotein E polymorphism and macroalbuminuria in patients with non-insulin dependent diabetes mellitus
Ha et al.
Nephrol Dial Transplant 1999;14:2144-2149.
ABSTRACT | FULL TEXT  

Rapid Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of ApoE in ApoE-Deficient Mice
Tsukamoto et al.
Arterioscler. Thromb. Vasc. Bio. 1999;19:2162-2170.
ABSTRACT | FULL TEXT  

Age-Dependent Association of Apolipoprotein E Genotype With Coronary and Aortic Atherosclerosis in Middle-Aged Men : An Autopsy Study
Ilveskoski et al.
Circulation 1999;100:608-613.
ABSTRACT | FULL TEXT  

APOE genotype, plasma lipids, lipoproteins, and AD in community elderly
Romas et al.
Neurology 1999;53:517-517.
ABSTRACT | FULL TEXT  

Modification of Type III VLDL, Their Remnants, and VLDL From ApoE-Knockout Mice by p-Hydroxyphenylacetaldehyde, a Product of Myeloperoxidase Activity, Causes Marked Cholesteryl Ester Accumulation in Macrophages
Whitman et al.
Arterioscler. Thromb. Vasc. Bio. 1999;19:1238-1249.
ABSTRACT | FULL TEXT  

Emerging Noninvasive Biochemical Measures to Predict Cardiovascular Risk
Pahor et al.
Arch Intern Med 1999;159:237-245.
ABSTRACT | FULL TEXT  

The Relationship Between Risk Factor Levels and Presence of Coronary Artery Calcification is Dependent on Apolipoprotein E Genotype
Kardia et al.
Arterioscler. Thromb. Vasc. Bio. 1999;19:427-435.
ABSTRACT | FULL TEXT  

Rapid Identification of Apolipoprotein E Genotypes by Multiplex Amplification Refractory Mutation System PCR and Capillary Gel Electrophoresis
Donohoe et al.
Clin. Chem. 1999;45:143-146.
FULL TEXT  

Relationship Between ApoE, MRI Findings, and Cognitive Function in the Cardiovascular Health Study
Kuller et al.
Stroke 1998;29:388-398.
ABSTRACT | FULL TEXT  

Prevalence of Apolipoprotein E Alleles in Healthy Subjects and Survivors of Ischemic Stroke : An Italian Case-Control Study
Margaglione et al.
Stroke 1998;29:399-403.
ABSTRACT | FULL TEXT  

Association of Apolipoprotein Genetic Polymorphisms With Plasma Cholesterol in a Japanese Rural Population : The Shibata Study
Zaman et al.
Arterioscler. Thromb. Vasc. Bio. 1997;17:3495-3504.
ABSTRACT | FULL TEXT  

Association of Apo E Polymorphism With Plasma Lipid Levels in a Multiethnic Elderly Population
Pablos-Mendez et al.
Arterioscler. Thromb. Vasc. Bio. 1997;17:3534-3541.
ABSTRACT | FULL TEXT  

Uptake of Type III Hypertriglyceridemic VLDL by Macrophages Is Enhanced by Oxidation, Especially After Remnant Formation
Whitman et al.
Arterioscler. Thromb. Vasc. Bio. 1997;17:1707-1715.
ABSTRACT | FULL TEXT  

Denaturing gradient-gel electrophoresis screening of familial defective apolipoprotein B-100 in a mixed Asian cohort: two cases of arginine3500 -> tryptophan mutation associated with a unique haplotype
Choong et al.
Clin. Chem. 1997;43:916-923.
ABSTRACT | FULL TEXT  

Polymorphism of the Apolipoprotein E Gene and Early Carotid Atherosclerosis Defined by Ultrasonography in Asymptomatic Adults
Cattin et al.
Arterioscler. Thromb. Vasc. Bio. 1997;17:91-94.
ABSTRACT | FULL TEXT  

Apolipoprotein E Alleles and Risk of Coronary Disease: A Meta-analysis
Wilson et al.
Arterioscler. Thromb. Vasc. Bio. 1996;16:1250-1255.
ABSTRACT | FULL TEXT  

Apolipoprotein E Polymorphism Is Associated With Segment-Specific Extracranial Carotid Artery Intima-Media Thickening
Terry et al.
Stroke 1996;27:1755-1759.
ABSTRACT | FULL TEXT  

Apolipoprotein E Polymorphism and LDL Size in a Biethnic Population
Haffner et al.
Arterioscler. Thromb. Vasc. Bio. 1996;16:1184-1188.
ABSTRACT | FULL TEXT  

Apolipoprotein E {epsilon}4 Is Associated With the Presence and Earlier Onset of Hemorrhage in Cerebral Amyloid Angiopathy
Greenberg et al.
Stroke 1996;27:1333-1337.
ABSTRACT | FULL TEXT  

Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the {epsilon}4 Allele for Apolipoprotein E
Reiman et al.
NEJM 1996;334:752-758.
ABSTRACT | FULL TEXT  

Statement on Use of Apolipoprotein E Testing for Alzheimer Disease
American College of Medical Genetics/American Soci et al.
JAMA 1995;274:1627-1629.
ABSTRACT  

A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease: Probable Benefits of Increasing Folic Acid Intakes
Boushey et al.
JAMA 1995;274:1049-1057.
ABSTRACT  

Polymorphisms of the Apolipoprotein E Gene and Severity of Coronary Artery Disease Defined by Angiography
Wang et al.
Arterioscler. Thromb. Vasc. Bio. 1995;15:1030-1034.
ABSTRACT | FULL TEXT