Association between apolipoprotein E polymorphism, lipids, and coronary artery disease in Tunisian type 2 diabetes

doi:10.1016/j.jacl.2008.08.441

Journal of Clinical Lipidology

Volume 2, Issue 5, October 2008, Pages 360-364

https://doi.org/10.1016/j.jacl.2008.08.441 Get rights and content

Background

The relationship between apolipoprotein E (ApoE) polymorphism, fasting lipid parameters, and coronary artery disease (CAD) is controversial.

Methods

We studied this relationship, for the first time, in Tunisian type 2 diabetic patients. The studied population comprised 157 type 2 diabetic patients (145 of them were not on any lipid-lowering drugs). Fasting lipids were measured by enzymatic methods and ApoE genotypes were determined by polymerase chain reaction–restriction fragment length polymorphism.

Results

Our results showed that the alleles E2, E3, and E4 were found in 4%, 88%, and 8% of patients, respectively. In the total type 2 diabetic population, no association was found between ApoE polymorphism, lipid parameters, and CAD. However, the E4 allele was associated with elevated low-density lipoprotein cholesterol concentration and with CAD in type 2 diabetic men.

Conclusion

The effect of ApoE polymorphism on CAD is gender-dependent in the Tunisian type 2 diabetic population. ApoE 4 allele may enhance atherogenesis indirectly by a strong effect on low-density lipoprotein cholesterol.

Section snippets

Background

Apolipoprotein E (ApoE) plays a requisite role in endogenous lipoprotein metabolism and tissue distribution.¹ It is a structural protein of chylomicrons, very-low-density lipoprotein, intermediate-density lipoprotein, and high-density lipoprotein, and serves as a ligand for the uptake of ApoE-containing lipoprotein by the hepatic ApoE receptor or low-density lipoprotein (LDL) receptor. The ApoE gene is polymorphic with three common alleles, E2, E3, and E4 encoding for three different isoforms.

Subjects

One-hundred fifty-seven type 2 diabetic patients (71 with CAD) ranging in age from 40 to 65 years old were recruited at the Service of Internal Medicine and Service of Cardiology in the Teaching Hospital of Monastir, Tunisia. Written or verbal informed consents were obtained from all patients and controls before the study. All written informed consent was not possible because the majority of eligible subjects in our study were illiterate. Diagnosis of diabetes was based on a history of

Results

Type 2 diabetic participants were genotyped for the ApoE polymorphism. Frequency of E2, E3, and E4 alleles were 0.04, 0.88, and 0.08, respectively. The majority of participants were E3E3 homozygous (0.80), although the genotype E2E2 was absent and only one subject had the E4E2 genotype.

Genotypes were condensed into three groups: E2 carrier group (E2E3), E4 carrier group (E3E4 and E4E4), and homozygous group (E3E3). The E2E4 did not belong to any of the groups mentioned and was not considered in

Discussion

Frequencies of ApoE alleles vary from one population to another, but E3 was, usually, the most frequent allele and E2 was the less frequent one.2, 4, 19 Compared to a Tunisian control population,⁷ the allele frequencies of ApoE polymorphism in our type 2 diabetic population were almost the same (0.07 vs 0.04 for E2, 0.84 vs 0.88 for E3, and 0.08 vs 0.08 for E4, respectively, in control and in type 2 diabetic populations). In general, but not usually, similar associations of ApoE with

Conclusions

The ApoE4 allele is associated with high LDL cholesterol level and CAD in Tunisian type 2 diabetic men. The high frequency of CAD in E4 carrier men is associated with elevated LDL cholesterol concentration. We agree with many studies that have shown that ApoE polymorphism may enhance atherogenesis indirectly by a strong affect on circulating lipids. In addition, this present study strengthens findings that ApoE polymorphism can be used to identify individuals with high risk of CAD and suggest a

Acknowledgments

This study was supported by a grant from the Ministère de l'Enseignement Supérieur (DGRST) and the Ministère de la recherche Scientifique et Technologique (UR ‘Nutrition Humaine et désordres métaboliques.' We would like to thank Dr. A. Girard-Globa and M. H. Ben Farhat for their stimulating discussion and encouragement.

References (28)

H.K. Das et al.
Isolation, characterization and mapping to chromosome 19 of the human apolipoprotein E gene
J Biol Chem.
(1985)
K.H. Weisgraber et al.
Abnormal lipoprotein receptor-binding activity of the human E apolipoprotein due to cysteine-arginine interchange at a single site
J Biol Chem.
(1982)
R. Frikke-Schmidt et al.
Context-dependent and invariant associations between lipids, lipoproteins and apolipoprotein E genotype
J Lipid Res.
(2000)
R. Jemaa et al.
Apolipoprotein E polymorphism in the Tunisian population: frequency and effect on lipid parameters
Clin Biochem.
(2006)
H. Kharrazi et al.
Association between apolipoprotein E polymorphism and coronary artery disease in the Kermanshah population in Iran
Clin Biochem.
(2006)
A. Kalina et al.
Association of plasma lipid levels with apolipoprotein E polymorphism in type 2 diabetes
Diabetes Res Clin Pract.
(2002)
G.D. Kolovou et al.
Apolipoprotein E polymorphism, age and coronary heart disease
Age Res Rev.
(2007)
R. Chaaba et al.
Association of plasma cholesteryl ester transfer protein activity and polymorphism with coronary artery disease extent in Tunisian type II diabetic patients
Clin Biochem.
(2005)
M. Smaoui et al.
Lipids and lipoprotein(a) concentrations in Tunisian type II diabetic patientsRelationship to glycemic control and coronary heart disease
J Diabetes Complications
(2004)
D. Gómez-Coronado et al.
Apolipoprotein E polymorphism in men and women from a Spanish population: allele frequencies and influence on plasma lipids and apolipoproteins
Atherosclerosis
(1999)

C.E. Tan et al.

Apo E polymorphism and lipid profile in three ethnic groups in the Singapore population

Atherosclerosis

(2003)

L. Djousse et al.

Apolipoprotein E polymorphism modifies the alcohol-HDL association observed in the National Heart, Lung and Blood Institute Family Heart Study

Am J Clin Nutr.

(2004)

J.V. Sorlí et al.

The effect of the APOE polymorphism on HDL-C concentrations depends on the cholesteryl ester transfer protein gene variation in a Southern European population

Clin Chim Acta.

(2006)

C. Lahoz et al.

Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study

Atherosclerosis

(2001)

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Apolipoprotein E (APOE) and cholesteryl ester transfer protein (CETP) play an important role in the lipid metabolism. Dyslipidemia is one of the complications that found in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to investigate the association of APOE and CETP TaqIB polymorphisms with T2DM and its related metabolic parameters in Southern Thai population. Study subjects were 241 T2DM patients and 275 healthy controls. The APOE and CETP TaqIB polymorphisms were analyzed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) technique. APOE polymorphism showed a statistical difference in allele frequencies (p = 0.025) and genotype distributions (p <0.001) between T2DM patients and healthy controls. The E4 carriers were associated with a significantly higher TC, and/or LDL-C levels compared to the E2 and E3 carriers, respectively in all subjects and healthy controls. Moreover, CETP TaqIB B2B2 genotype was significantly higher HDL-C levels compared with B1B1, and B1B2 genotypes in all subjects, and T2DM patients. Multiple logistic regression analysis showed that APOE and CETP TaqIB polymorphisms were not associated with T2DM. In conclusion, APOE and CETP TaqIB polymorphisms might not be the genetic risk factors for T2DM in Southern Thai population, however, APOE and CETP TaqIB polymorphisms were associated with serum lipids in healthy controls and T2DM, respectively.
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Type 2 diabetes mellitus (T2DM) prevalence has increased in Tunisian population from 9.9% in 1996 to 15.1% in 2014 (Ben Romdhane et al., 2014; Bouguerra et al., 2007; Chaaba et al., 2008).
Recent in vitro researches have shown that plasma Lp(a) can be reduced using a proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitory monoclonal antibody. In our clinical study we tried to investigate the association between plasma Lp(a) and PCSK9 in Type 2 diabetic patients with elevated plasma Lp(a), and to check whether such an association would be related to LDL-receptor (LDL-R) levels.
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Lp(a) has been proposed as a contributing factor to the accelerated development of macrovascular complications in T2DM. Its synergic effect with PCSK9 may explain the enhanced atherogenicity in T2DM patients.
Relationship of apolipoprotein E polymorphism with lipid profiles in atherosclerotic coronary artery disease
2013, Egyptian Heart Journal
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Apolipoprotein E (ApoE) is a plasma glycoprotein and helps lipoprotein clearance from circulation.7 ApoE is a structural protein of chylomicrons, very-low-density lipoproteins, intermediate-density lipoproteins, and high-density lipoproteins, and serves as a ligand for the uptake of ApoE-containing lipoproteins by the hepatic ApoE receptor or low-density lipoprotein (LDL) receptor.6 Owing to the complexity of the apoE structure–function, it is not surprising that mutations and polymorphisms of the ApoE gene can have an important impact on protein function.
The aim was to determine the relationship between apolipoprotein E (ApoE) gene polymorphisms and lipid profile in patients with coronary artery diseases (CAD), and its role in the prediction of the severity of carotid and coronary atherosclerosis.
One hundred patients were classified by coronary angiography: 80 patients with CAD and 20 controls (normal coronary angiography). Clinical data, carotid sonography, blood lipid profiles and ApoE genotyping (PCR-RFLP) were assessed. CAD patients had significantly increased plasma lipid profiles and carotid intimal-wall thickness (IMT) versus controls. In CAD patients; ApoE genotype frequencies were E3/E3 = 62.50%, E2/E3 = 18.75%, E3/E4 = 17.50%, E2/E4 = 1.25%, E4/E4 = 0 and E2/E2 = 0. But, E3/E4 genotype was significantly higher than controls (P < 0.05). Also, in CAD patients; ApoE allele frequencies were E3 = 80.6%, E2 = 10.0% and E4 = 9.4% but, ApoE4 alleles were associated with higher cholesterol (P = 0.034) and LDL-c (P = 0.003), while ApoE2 alleles were associated with higher triglycerides (P = 0.037) versus ApoE3 alleles. However, odds ratio of CAD patients had higher risk with E2/E3 genotypes (2.5-fold), E2 alleles (2.2-fold) and E4 alleles (2.1-fold). Moreover, CAD patients with ApoE4 alleles had significantly higher carotid IMT (1.23 ± 0.26 mm vs 0.97 ± 0.2 mm ApoE3, P = 0.006; however, non-significant vs 1.10 ± 0.40 mm ApoE2 and also, ApoE2 vs ApoE3 alleles, P = 0.633) and left anterior descending (LAD) coronary artery stenosis (vs ApoE3 alleles, P = 0.016).
Ischemic patients with carotid and coronary atherosclerosis had significantly higher integration of dyslipidemia and ApoE alleles (ApoE2 with hypertriglyceridemia and ApoE4 with hypercholesterolemia and higher LDL-c). ApoE polymorphism may be an important diagnostic risk biomarker and may implicate therapeutic intervention in atherosclerotic ischemic patients.
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Original articleAssociation between apolipoprotein E polymorphism, lipids, and coronary artery disease in Tunisian type 2 diabetes

Background

Methods

Results

Conclusion

Section snippets

Background

Subjects

Results

Discussion

Conclusions

Acknowledgments

J Biol Chem.

J Biol Chem.

J Lipid Res.

Clin Biochem.

Clin Biochem.

Diabetes Res Clin Pract.

Age Res Rev.

Clin Biochem.

J Diabetes Complications

Atherosclerosis

Atherosclerosis

Am J Clin Nutr.

Clin Chim Acta.

Atherosclerosis

Original article
Association between apolipoprotein E polymorphism, lipids, and coronary artery disease in Tunisian type 2 diabetes