Association of APOE genotype with carotid atherosclerosis in men and women

Abstract

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. 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. 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 (1Wilson P.W.F. Myers R.H. Larson M.G. Ordovas J.M. Wolf P.A. Schaefer E.J. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study.J. Am. Med. Assoc. 1994; 272: 1666-1671Crossref PubMed Scopus (463) Google Scholar). Both E2 and E4 are also associated with increases in plasma triglycerides (2Dallongeville J. Lussier-Cacan S. Davignon J. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis.J. Lipid Res. 1992; 33: 447-454Abstract Full Text PDF PubMed Google Scholar) and increased cardiovascular disease (CVD) risk (1Wilson P.W.F. Myers R.H. Larson M.G. Ordovas J.M. Wolf P.A. Schaefer E.J. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study.J. Am. Med. Assoc. 1994; 272: 1666-1671Crossref PubMed Scopus (463) Google Scholar, 3Wilson P.W.F. Schaefer E.J. Larson M.G. Ordovas J.M. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1250-1255Crossref PubMed Scopus (507) Google Scholar), although the E2 allele was associated with a lower CVD risk in women in the Framingham Study (1Wilson P.W.F. Myers R.H. Larson M.G. Ordovas J.M. Wolf P.A. Schaefer E.J. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study.J. Am. Med. 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Data from the Framingham Heart Study (9Fox C.S. Polak J.F. Chazaro I. Cupples A. Wolf P.A. D'Agostino R.A. O'Donnell C.J. Genetic and environmental contributions to atherosclerosis phenotypes in men and women: heritability of carotid intima-media thickness in the Framingham Heart Study.Stroke. 2003; 34: 397-401Crossref PubMed Scopus (177) Google Scholar) and other studies (10Hunt K.J. Duggirala R. Goring H.H. Williams J.T. Almasy L. Blangero J. O'Leary D.H. Stern M.P. Genetic basis of variation in carotid artery plaque in the San Antonio Family Heart Study.Stroke. 2002; 33: 2775-2780Crossref PubMed Scopus (63) Google Scholar) 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 (11Beilby J.P. Hunt C.C. Palmer L.J. Chapman C.M. Burley J.P. McQuillan B.M. Thompson P.L. Hung J. 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. 2003; 34: 869-874Crossref PubMed Scopus (44) Google Scholar, 12Karvonen J. Kauma H. Kervinen K. Ukkola O. Rantala M. Paivansalo M. Savolainen M.J. Kesaniemi Y.A. Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men.J. Hypertens. 2002; 20: 2371-2378Crossref PubMed Scopus (39) Google Scholar, 13Haraki T. Takegoshi T. Kitoh C. Wakasugi T. Saga T. Hirai J.I. Aayama T. Inazu A. Mabuchi H. Carotid artery intima-media thickness and brachial artery flow-mediated vasodilation in asymptomatic Japanese male subjects amongst apolipoprotein E phenotypes.J. Intern. Med. 2002; 252: 114-120Crossref PubMed Scopus (34) Google Scholar, 14Djousse L. Myers R.H. Province M.A. Hunt S.C. Eckfeldt J.H. Evans G. Peacock J.M. Ellison R.C. Influence of apolipoprotein E, smoking, and alcohol intake on carotid atherosclerosis. National Heart, Lung, and Blood Institute Family Heart Study.Stroke. 2002; 33: 1357-1361Crossref PubMed Scopus (90) Google Scholar, 15Slooter A.J. Bots M.L. Havekes L.M. del Sol A.I. Cruts M. Grobbee D.E. Hofman A. Van Broeckhoven C. Witteman J.C. van Duijn C.M. Apolipoprotein E and carotid artery atherosclerosis. The Rotterdam Study.Stroke. 2001; 32: 1947-1952Crossref PubMed Scopus (71) Google Scholar, 16Ilveskoski E. Loimaala A. Mercury M.F. Lehtimaki T. Pasanen M. Nenonen A. Oja P. Bond M.G. Koivula T. Karhunen P.J. Vuori I. Apolipoprotein E polymorphism and carotid intima media thickness in a random sample of middle-aged men.Atherosclerosis. 2000; 153: 147-153Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 17Horejsi B. Spacil J. Ceska R. Vrablik M. Haas T. Horinek A. The independent correlation of the impact of lipoprotein(a) levels and apolipoprotein E polymorphism on carotid artery intima thickness.Int. Angiol. 2000; 19: 331-336PubMed Google Scholar, 18Hanon O. Girerd X. Luong V. Jeunemaitre X. Laurent S. Safar M.E. Association between the apolipoprotein E polymorphism and arterial wall thickness in asymptomatic adults.J. Hypertens. 2000; 18: 431-436Crossref PubMed Scopus (30) Google Scholar, 19Zannad F. Visvikis S. Gueguen R. Sass R. Chapet O. Herbeth B. Siest G. Genetics strongly determines the wall thickness of the left and right carotid arteries.Hum. Genet. 1998; 103: 183-188Crossref PubMed Scopus (90) Google Scholar, 20Sass C. Zannad F. Herbeth B. Salah D. Chapet O. Siest G. Visvikis S. 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. 1998; 140: 89-95Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, K. M. T. K. T. H. of polymorphism of apolipoprotein E and enzyme on arterial wall 1997; PubMed Scopus Google Scholar, I. L. M. R. J. J. M. R. M. association of apolipoprotein E polymorphism with disease in with and Med. 1997; PubMed Scopus Google Scholar, L. M. M. M. M. S. E. M. F. of the apolipoprotein E gene and carotid atherosclerosis defined by in asymptomatic Thromb. Vasc. Biol. 1997; PubMed Scopus Google Scholar, Howard G. M. Bond M.G. Apolipoprotein E polymorphism is associated with carotid artery intima-media 1996; PubMed Scopus Google Scholar, M. I. S. Jr., A. W. E. Relationship of the apolipoprotein E polymorphism with carotid artery J. Genet. 1995; Google Scholar). The aim of the was to determine the association between APOE genotype and carotid atherosclerosis and to assess other CVD risk factors modify this association in the Framingham Heart The Framingham in with the of men and women between the of and in this were in the of the Framingham Heart in with the of men and women were and of of the and in from to The study of the Framingham and studies has been in M. P.M. of coronary heart disease in The Framingham Offspring J. PubMed Scopus Google Scholar). were in study examination cycle 6 A total of of underwent carotid APOE genotype data were for The was by the of Ultrasound studies were and to a J.F. O'Leary D.H. Kronmal R.A. Wolfson S.K. Bond M.G. J.M. P.J. of carotid artery atherosclerosis in the of disease to stroke and PubMed Scopus Google Scholar, D.H. Polak J.F. Kronmal R.A. Bond M.G. Wolfson Jr., S.K. W. J.M. P.J. and of carotid artery disease in the Cardiovascular Health The Collaborative Research 1992; PubMed Scopus Google Scholar). was a for the common artery and a for the internal carotid artery were the common carotid artery and in the of the internal carotid artery A of the and was by one of the the IMT in the and were and IMT were defined as the of the IMT for the right and left were to Data for the of the IMT for and IMT were also (9Fox C.S. Polak J.F. Chazaro I. Cupples A. Wolf P.A. D'Agostino R.A. O'Donnell C.J. Genetic and environmental contributions to atherosclerosis phenotypes in men and women: heritability of carotid intima-media thickness in the Framingham Heart Study.Stroke. 2003; 34: 397-401Crossref PubMed Scopus (177) Google Scholar). by correlation for the and and IMT were and A of as and was by the in the were of was defined as in the were the of stenosis was on the The of carotid stenosis from on studies was to that in other studies of was from of whole as A for from Res. PubMed Scopus Google Scholar). APOE was as by and of apolipoprotein E by gene and with Lipid Res. Full Text PDF PubMed Google Scholar). A of the APOE gene the polymorphic was by in a and of apolipoprotein E by gene and with Lipid Res. Full Text PDF PubMed Google Scholar). was for and by of for for and for The were with of and the by on an the was with for and were by with defined APOE genotype the APOE2 group subjects the or E3/E2 the APOE3 group the and the APOE4 group the or E4/E4 genotype. with the genotype = were from the Data the and examination were from the examination cycle L.A. D'Agostino R.B. D. The Framingham Heart of Cardiovascular Cardiovascular National Heart, Lung, and Blood Scholar). plasma was measured in with a was defined by or of or total cholesterol, cholesterol, and triglycerides were measured as (1Wilson P.W.F. Myers R.H. Larson M.G. Ordovas J.M. Wolf P.A. Schaefer E.J. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study.J. Am. Med. Assoc. 1994; 272: 1666-1671Crossref PubMed Scopus (463) Google Scholar). LDL cholesterol were with the were as if during the and were the of The of to was and were measured with the in an and was as in by the of in was defined as to groups and to of groups were of was used to determine the carotid IMT APOE for for men and was to determine the association between and the presence of were for in A was determine the association between APOE genotype and carotid atherosclerosis, the APOE genotype and of the between groups were for by the also a of the data in studies the association between APOE genotype and carotid atherosclerosis. studies with a the for The Scholar). and were The was by of the sample by are in The of APOE alleles were and for alleles and E4, and the were with the APOE genotype = the of APOE was and for E2/E2, E4/E3, and The carotid IMT and the prevalence of carotid stenosis were higher in by = = genotype cholesterol cholesterol cholesterol IMT IMT are as or common carotid artery intimal-medial internal carotid artery intimal-medial in a Data are as or common carotid artery intimal-medial internal carotid artery intimal-medial In men and women, LDL cholesterol in the APOE2 group was lower than in the APOE3 and APOE4 in men, triglycerides were higher in the APOE4 group than in the APOE2 whereas in women, cholesterol in the APOE2 group was higher than in the APOE4 group. other were were with results in the Framingham Study (1Wilson P.W.F. Myers R.H. Larson M.G. Ordovas J.M. Wolf P.A. Schaefer E.J. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study.J. Am. Med. Assoc. 1994; 272: 1666-1671Crossref PubMed Scopus (463) Google Scholar). the between carotid IMT and carotid The correlation between carotid stenosis as or and IMT or IMT were and in men and and in women, the IMT in subjects and with carotid stenosis 25% were and in men and and in women, was in the carotid IMT or in the of with carotid stenosis APOE genotype groups carotid and carotid stenosis APOE genotype groups in men and = = = cholesterol LDL cholesterol cholesterol IMT IMT Carotid = = = cholesterol LDL cholesterol cholesterol IMT IMT Carotid are as or in a Data are as or examined of the of carotid IMT APOE groups by for and other In men, were in or IMT APOE In women, the and IMT in the APOE2 group were lower than of the APOE4 and APOE3 was between APOE2 and APOE4 for IMT and between APOE2 and APOE3 for plasma in the the were that the in plasma and carotid IMT APOE genotype groups in men and compared with APOE4 compared with APOE4 compared with APOE3 compared with APOE3 are as were as for and for smoking, diabetes, and of for and LDL cholesterol, and compared with APOE4 compared with APOE3 genotype. in a Data are as were as for and for smoking, diabetes, and of for and LDL cholesterol, and of APOE genotype groups for stenosis 25% are in In men, association between APOE genotype and carotid stenosis was In women, the APOE2 group was associated with a lower prevalence of carotid stenosis compared with the APOE3 and APOE4 association for The interaction between APOE2 and was (P = The were a of for carotid were of with confidence not and for carotid stenosis by APOE genotype in men and APOE3 = APOE2 = APOE4 = APOE3 = APOE2 = APOE4 = were as for and for smoking, diabetes, and of for and LDL cholesterol, and in a were as for and for smoking, diabetes, and of for and LDL cholesterol, and A of diabetes was in the association between APOE genotype and IMT in men (P = but not in The IMT APOE groups in men by diabetes is in groups were in men. in diabetic men, the IMT of the APOE4 group was significantly higher than that of the APOE3 and APOE2 groups for the interaction was not (P = although the IMT of the APOE4 group mm) was significantly higher than that of the APOE3 group mm) (P = was associated with higher IMT in APOE4 men (P = whereas in women, the association between diabetes and carotid IMT was (P = of the APOE genotype. was for a interaction of smoking, or on the association between APOE genotype and carotid IMT or of the results used the of the IMT of the of the In this that between APOE genotype and carotid atherosclerosis are modified by diabetes and by In women, the E2 allele was associated with lower and IMT and lower prevalence of carotid The association with IMT was plasma but the association with stenosis was for The E4 allele was associated with higher IMT in diabetic men. The association between the E2 allele and carotid atherosclerosis in women is with in the Framingham Heart Study a association between the E2 allele and prevalent CVD in women (1Wilson P.W.F. Myers R.H. Larson M.G. Ordovas J.M. Wolf P.A. Schaefer E.J. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study.J. Am. Med. Assoc. 1994; 272: 1666-1671Crossref PubMed Scopus (463) Google Scholar). a to assess the of results with In the of data from women, there was association between APOE genotype and carotid atherosclerosis determined as the measure of IMT or a and APOE4 and 95% for carotid atherosclerosis in studies APOE3 group is the and association by random and the results of this vs. vs. confidence Carotid atherosclerosis are as to with the of increased thickness carotid stenosis in a confidence Carotid atherosclerosis are as to with the of increased thickness carotid stenosis In men, a but association between the E2 allele and carotid The E2 allele was not significantly associated with carotid although to associated with higher IMT and with lower In the for men, there was an and association between the E2 allele and IMT and a and association between the E2 allele and carotid atherosclerosis as a results are with that APOE genotype Howard G. M. Bond M.G. Apolipoprotein E polymorphism is associated with carotid artery intima-media 1996; PubMed Scopus Google Scholar) and risk factors M.A. R. D.H. M. of risk factors with intimal-medial thickness of the carotid 1999; PubMed Scopus Google Scholar) are associated with a carotid IMT and the that the between and in regions of arterial as the to and factor 1995; PubMed Scopus Google Scholar). as in the is to wall the wall the that in with increases and the of to the arterial wall A. C. C. V. G. P.L. A. Association between intima-media thickness and wall in common carotid arteries in healthy male 1996; PubMed Scopus Google Scholar). the in the between APOE genotype and and The of on the association between APOE2 and carotid atherosclerosis is not although of the E2 allele a higher of lipoprotein J. L. Visvikis S. M. G. M. G. of E on plasma triglyceride levels in male with and a of myocardial The Atherosclerosis Research Study.Atherosclerosis. 1999; Full Text Full Text PDF PubMed Scopus (44) Google Scholar). In men, the associated with in subjects with lower cholesterol, whereas in women, this by higher cholesterol The higher in men compared with women C. D. J. A. C. P. J.P. in of Thromb. Vasc. Biol. 1999; 19: PubMed Scopus Google Scholar) also play a role in this APOE gene in higher apoE and a R.A. M. R.C. G. apolipoprotein E gene by in the the Biol. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). not a association between the E4 allele and carotid atherosclerosis. The association between the E4 allele and higher carotid IMT has been in studies T. Takegoshi T. Kitoh C. Wakasugi T. Saga T. Hirai J.I. Aayama T. Inazu A. Mabuchi H. Carotid artery intima-media thickness and brachial artery flow-mediated vasodilation in asymptomatic Japanese male subjects amongst apolipoprotein E phenotypes.J. Intern. Med. 2002; 252: 114-120Crossref PubMed Scopus (34) Google Scholar, I. L. M. R. J. J. M. R. M. association of apolipoprotein E polymorphism with disease in with and Med. 1997; PubMed Scopus Google Scholar, L. M. M. M. M. S. E. M. F. of the apolipoprotein E gene and carotid atherosclerosis defined by in asymptomatic Thromb. Vasc. Biol. 1997; PubMed Scopus Google Scholar, Howard G. M. Bond M.G. Apolipoprotein E polymorphism is associated with carotid artery intima-media 1996; PubMed Scopus Google Scholar), although have to an association (11Beilby J.P. Hunt C.C. Palmer L.J. Chapman C.M. Burley J.P. McQuillan B.M. Thompson P.L. Hung J. 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. 2003; 34: 869-874Crossref PubMed Scopus (44) Google Scholar, 15Slooter A.J. Bots M.L. Havekes L.M. del Sol A.I. Cruts M. Grobbee D.E. Hofman A. Van Broeckhoven C. Witteman J.C. van Duijn C.M. Apolipoprotein E and carotid artery atherosclerosis. The Rotterdam Study.Stroke. 2001; 32: 1947-1952Crossref PubMed Scopus (71) Google Scholar, 16Ilveskoski E. Loimaala A. Mercury M.F. Lehtimaki T. Pasanen M. Nenonen A. Oja P. Bond M.G. Koivula T. Karhunen P.J. Vuori I. Apolipoprotein E polymorphism and carotid intima media thickness in a random sample of middle-aged men.Atherosclerosis. 2000; 153: 147-153Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 17Horejsi B. Spacil J. Ceska R. Vrablik M. Haas T. Horinek A. The independent correlation of the impact of lipoprotein(a) levels and apolipoprotein E polymorphism on carotid artery intima thickness.Int. Angiol. 2000; 19: 331-336PubMed Google Scholar, 18Hanon O. Girerd X. Luong V. Jeunemaitre X. Laurent S. Safar M.E. Association between the apolipoprotein E polymorphism and arterial wall thickness in asymptomatic adults.J. Hypertens. 2000; 18: 431-436Crossref PubMed Scopus (30) Google Scholar, 19Zannad F. Visvikis S. Gueguen R. Sass R. Chapet O. Herbeth B. Siest G. Genetics strongly determines the wall thickness of the left and right carotid arteries.Hum. Genet. 1998; 103: 183-188Crossref PubMed Scopus (90) Google Scholar, 20Sass C. Zannad F. Herbeth B. Salah D. Chapet O. Siest G. Visvikis S. 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. 1998; 140: 89-95Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, K. M. T. K. T. H. of polymorphism of apolipoprotein E and enzyme on arterial wall 1997; PubMed Scopus Google Scholar, I. L. M. R. J. J. M. R. M. association of apolipoprotein E polymorphism with disease in with and Med. 1997; PubMed Scopus Google Scholar). In the the E4 allele was not associated with carotid IMT or carotid atherosclerosis In although was associated with a in IMT in men, the E4 allele was significantly associated with higher carotid IMT in diabetic men. has been G. T. Apolipoprotein E genotype and carotid atherosclerosis in diabetes 2003; 20: Google Scholar) and in with peripheral arterial disease B. R. L. D. E diabetes, and peripheral arterial disease in older men. The 2000; 19: PubMed Scopus Google Scholar), for myocardial X. X. L. H. allele increases the risk for myocardial in diabetes 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and for L. Manolio T.A. L. The role of APOE in of other risk factors for in Am. Med. Assoc. 1999; PubMed Scopus Google Scholar). The of the E4 allele and diabetes the of and the risk of carotid atherosclerosis. have in the an interaction between APOE genotype and on and levels in men R. S. Cupples L.A. Wilson P.W.F. Schaefer E.J. D. Ordovas J.M. modulates the association APOE and in Res. 2003; PubMed Scopus Google Scholar). data that the E4 allele risk higher in men with the examined a for is that interaction is the examined during are for the in the presence and of between APOE genotype and carotid atherosclerosis studies P.M. of with 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). in the study of carotid atherosclerosis or carotid carotid interaction and sample and of diabetes to the J.M. E.J. variation of cholesterol and intake and 1999; PubMed Scopus Google Scholar) and R.W. M.A. F. S. A. of genotype on Thromb. Vasc. Biol. 2002; PubMed Scopus Google Scholar) also modify the association between APOE genotype and plasma study is in men and women from a with a of risk factor and prevalence of with other in environmental factors of the of study have in the of carotid stenosis, although that this random and to a APOE2 genotype was associated with lower carotid atherosclerosis in women, the of the role of this genotype on CVD in women (1Wilson P.W.F. Myers R.H. Larson M.G. Ordovas J.M. Wolf P.A. Schaefer E.J. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study.J. Am. Med. Assoc. 1994; 272: 1666-1671Crossref PubMed Scopus (463) Google Scholar). The of this interaction to APOE4 genotype was significantly associated with a higher IMT in diabetic men. this with the association between APOE genotype and atherosclerosis in diabetic and have and