Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults

Viiri, Leena E.; Raitakari, Olli T.; Kähönen, Mika; Rontu, Riikka; Juonala, Markus; Hutri‐Kähönen, Nina; Marniemi, Jukka; Viikari, Jorma; Karhunen, Pekka J.; Lehtimäki, Terho

doi:10.1194/jlr.m600033-jlr200

Cited by 18 publications

(16 citation statements)

References 31 publications

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“…35 Furthermore, a recent study by Viiri and coworkers found no significant association between the APOE promoter genotypes and carotid IMT, brachial FMD or CAC within the APOE 3/ 3 carriers. 36 The present study differs from that of previous studies in that we examined the association between common APOE polymorphism and carotid IMT, brachial FMD and CAC in the youngest population studied thus far (ie, young adults aged 24-39 years). The well-known link between the APOE phenotypes and serum lipids was clear but there was no association between ultrasound markers and APOE polymorphism.…”

Section: Discussioncontrasting

confidence: 49%

“…Furthermore, very little is known about whether the APOE locus affects interindividual variation of brachial FMD or CAC. 35,36 Therefore, we examined the relation of common APOE polymorphism to carotid IMT, brachial FMD and CAC in 1,188 young adults (aged 24-39 years) participating in the Cardiovascular Risk In Young Finns Study. In the same population, the lipid and lipoprotein levels as well as blood pressure were examined according to the APOE phenotypes.…”

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Relation of Apolipoprotein E Polymorphism to Markers of Early Atherosclerotic Changes in Young Adults The Cardiovascular Risk in Young Finns Study

Grönroos

Raitakari

Kähönen

et al. 2008

Circ J

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ltrasonic methods, such as measurements of carotid artery intima-media thickness (IMT), carotid artery compliance (CAC) and brachial artery flow-mediated dilatation (FMD), have gained increasing acceptance in the assessment of early atherosclerotic changes. Especially, carotid IMT is widely used as a measure of subclinical atherosclerosis, but brachial FMD responses also predict future cardiovascular events in patient groups and decreased arterial elasticity has been implicated as an independent predictor of cardiovascular events and mortality in high-risk individuals. [1][2][3][4][5][6] Convential cardiovascular risk factors (eg, high low-density lipoprotein (LDL)-cholesterol), in turn, have been associated with increased carotid IMT, decreased brachial FMD and decreased arterial elasticity. 1,[7][8][9][10][11][12][13] Circulation Journal Vol.72, January 2008 Genetic factors play a role in the pathogenesis of atherosclerosis, partly by influencing plasma lipoprotein concentrations. 4,[14][15][16][17][18] Heritability estimates of interindividual differences in IMT range from 30% to 40% but the specific genes contributing to this variability are unknown. 4,19,20 Of the many candidate genes investigated for their possible influence on the risk of coronary artery disease, the gene for apolipoprotein E (APOE) has received much attention 4 and APOE polymorphism, in general, is considered an important genetic determinant and risk factor for coronary heart disease. 21,22 Genetic variation in the polymorphic APOE locus significantly affects plasma lipoprotein concentrations 17,19,20,23 but the effects on IMT, FMD or CAC are inadequately known. Several studies have examined the APOE gene with respect to carotid IMT but results have been inconclusive. 24,25 An association between the 4 allele and higher IMT or the 2 allele and lower IMT has been found in some, but not all, studies. 16,[26][27][28][29][30][31][32][33][34] Subjects in most previous studies have been middle-aged or older or have represented diverse patient groups. Furthermore, very little is known about whether the APOE locus affects interindividual variation of brachial FMD or CAC. 35,36 Therefore, we examined the relation of common APOE polymorphism to carotid IMT, brachial FMD and CAC in 1,188 young adults (aged 24-39 years) participating in the Cardiovascular Risk In Young Finns Study. In the same population, the lipid and lipoprotein levels as well as blood pressure were examined according to the APOE phenotypes. J 2008; 72: 29 -34 (Received February 27, 2007; revised manuscript received August 24, 2007; accepted September 3, 2007) Circ Relation of Apolipoprotein E Polymorphism to Markers of Early Atherosclerotic Changes in Young AdultsThe Cardiovascular Risk in Young Finns Study Paula Grönroos, MD, PhD* , **; Olli T. Raitakari, MD, PhD † ; Mika Kähönen, MD, PhD † † ; Nina Hutri-Kähönen, MD, PhD ‡ ; Markus Juonala, MD, PhD ‡ ‡ ; Jukka Marniemi, PhD § ; Jorma Viikari, MD, PhD § § ; Terho Lehtimäki, MD, PhD** Background Carotid artery intima-me...

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Section: Discussioncontrasting

confidence: 49%

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Relation of Apolipoprotein E Polymorphism to Markers of Early Atherosclerotic Changes in Young Adults The Cardiovascular Risk in Young Finns Study

Grönroos

Raitakari

Kähönen

et al. 2008

Circ J

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“…In nonsmokers, the ϩ113C-allele carriers had larger lesion areas compared with G/G, which agrees with our previous results showing higher cholesterol concentrations in C-allele carriers in a longitudinal study 8 but disagrees with the results from our functional experiments. It is central to remember that based on association analyses, it is difficult to make definite conclusions about the causality of SNPs.…”

Section: Discussioncontrasting

confidence: 35%

“…4 The common APOE 2/3/4 polymorphism, 5,6 as well as 2 promoter polymorphisms of the APOE gene, Ϫ219G/T and ϩ113G/C, and their haplotype are known to have impact on serum lipid levels. 7,8 In addition to single nucleotide polymorphisms (SNPs), the APOE gene haplotype has been shown to have clinical impact. The APOE Ϫ219G/ϩ113G/3 haplotype has previously been associated with increased risk of neuropathologically verified Alzheimer disease.…”

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Interactions of Functional Apolipoprotein E Gene Promoter Polymorphisms With Smoking on Aortic Atherosclerosis

Viiri

Ilveskoski

et al. 2008

Circ Cardiovasc Genet

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Background-Apolipoprotein E gene (APOE) interacts with environmental factors in defining risk for atherosclerosis. We studied whether the APOE 2/3/4 genotype or APOE promoter polymorphisms Ϫ219G/T and ϩ113G/C might interact with smoking on the development of fatty streaks. We also studied the previously unknown effects of ϩ113G/C on transcriptional activity. Methods and Results-The fatty streak areas of aorta were measured morphometrically in subjects of the Helsinki Sudden Death Study. Within APOE 3/3 subjects, there was a strong interaction between smoking and both Ϫ219G/T (Pϭ0.009) and ϩ113G/C (Pϭ0.003) promoter polymorphisms on abdominal aorta fatty streak area: the Ϫ219T-and ϩ113C-allele carriers had larger lesion areas compared with G/G (12.7% versus 5.9%, Pϭ0.007; 12.9% versus 6.3%, Pϭ0.010, respectively) within nonsmokers. Within smokers, the associations were inverse. Moreover, smoking increased the fatty streak area within Ϫ219G/G or ϩ113G/G genotypes and Ϫ219G/ϩ113G/3 haplotype carriers. Functional studies in reporter assay showed that in comparison with the ϩ113G allele, the ϩ113C allele had higher transcriptional activity and bound transcription factors from liver cell nuclear extract with significantly lower affinity. Conclusions-In middle-aged Finnish men with APOE 3/3 genotype, the APOE promoter polymorphisms Ϫ219G/T and ϩ113G/C interact with smoking in modulating aortic atherosclerosis. The ϩ113G/C polymorphism has an effect on transcriptional activity. (Circ Cardiovasc Genet. 2008;1:107-116.)

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“…11 Carriers of the À219G/ G-genotype had 10 -20% higher apoE plasma concentrations compared to À219T/T genotype. 12 Moreover, the À219G/T polymorphism has been reported to associate with atherogenic lipid and lipoprotein profile, 13,14 as well as with coronary atherosclerosis. 15 However, the role of these SNPs in IS and in cerebral atherosclerosis has not been studied before.…”

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confidence: 99%

Associations of apolipoprotein E gene with ischemic stroke and intracranial atherosclerosis

et al. 2008

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The apolipoprotein E (APOE) e4 allele is associated with elevated cholesterol and risk of atherosclerosis. However, its role in ischemic stroke (IS) remains controversial. We investigated a possible link between IS or the severity of intracranial atherosclerosis and the APOE promoter polymorphisms À219G/T and þ 113G/C, involved in regulating APOE transcription. We genotyped subjects from a multicentric Belgian case-control study, including 237 middle-aged patients with IS due to small-or large-vessel atherosclerotic stroke and 326 ethnicity-and gender-matched controls and a Finnish autopsy series of 1004 non-stroke cases, who had received a quantitative score of atherosclerosis in the circle of Willis. The APOE e4 þ genotype did not associate with IS, but was related to more severe intracranial atherosclerosis score in men (5.4 vs 4.6, P ¼ 0.044). Within the most common APOE e3/e3 genotype group, the risk of IS associated with the G-allele of the tightly linked À219G/T (OR ¼ 6.2; 95% CI: 1.6 -24.3, P ¼ 0.009) and þ 113G/C (OR ¼ 7.1; 95% CI: 1.7 -29.9, P ¼ 0.007) promoter polymorphisms. There was no difference in the severity of intracranial atherosclerosis between À219G/G genotype carriers and non-carriers. This study suggests a multifaceted role of apoE on the risk of cerebrovascular diseases. The APOE e4 þ genotype did not predict the risk of IS but was associated with severity of subclinical intracranial atherosclerosis in men on the autopsy study. In contrast, the promoter variants were significant predictors of IS, suggesting that quantitative rather than qualitative variation of apoE is related to IS.

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Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults

Cited by 18 publications

References 31 publications

Relation of Apolipoprotein E Polymorphism to Markers of Early Atherosclerotic Changes in Young Adults The Cardiovascular Risk in Young Finns Study

Relation of Apolipoprotein E Polymorphism to Markers of Early Atherosclerotic Changes in Young Adults The Cardiovascular Risk in Young Finns Study

Interactions of Functional Apolipoprotein E Gene Promoter Polymorphisms With Smoking on Aortic Atherosclerosis

Associations of apolipoprotein E gene with ischemic stroke and intracranial atherosclerosis

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