Apolipoprotein E gene polymorphisms as risk factors for carotid atherosclerosis

Irena Zurnić; Tamara Djurić; Igor Končar; Aleksandra Stanković; Dragan Dinčić; Maja Živković

doi:10.2298/2402

Irena Zurnić Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, University of Belgrade, Belgrade, Serbia
Tamara Djurić Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, University of Belgrade, Belgrade, Serbia
Igor Končar Clinic for Vascular and Endovascular Surgery, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
Aleksandra Stanković Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, University of Belgrade, Belgrade, Serbia
Dragan Dinčić Clinic for Urgent Internal Medicine, Military Medical Academy, Belgrade, Serbia; Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
Maja Živković Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, University of Belgrade, Belgrade, Serbia

DOI: https://doi.org/10.2298/2402

Keywords: genetic predisposition to disease, carotid artery disease, polymorphism, genetic, apolipoproteins e,

Abstract

Background/Aim. Atherosclerosis is still the leading cause of death in Western world. Development of atherosclerotic plaque involves accumulation of inflammatory cells, lipids, smooth muscle cells and extracellular matrix proteins in the intima of the vascular wall. Apolipoprotein E participates in the transport of exogenous cholesterol, endogenously synthesized lipids and triglycerides in the organism. Apolipoprotein E gene has been identified as one of the candidate genes for atherosclerosis. Previous studies in different populations have clearly implicated apolipoprotein E genetic variation (ε polymorphisms) as a major modulator of low density lipoprotein cholesterol levels. Data considering apolipoprotein E polymorphisms in relation to carotid atherosclerosis gave results that are not in full compliance. The aim of present study was to investigate the apolipoprotein E polymorphisms in association with carotid plaque presence, apolipoprotein E and lipid serum levels in patients with carotid atherosclerosis from Serbia. Methods. The study group enrolled 495 participants: 285 controls and 210 consecutive patients with carotid atherosclerosis who underwent carotid endarterectomy. Genotyping of apolipoprotein E polymorphisms were done using polymerase chain reaction and restriction fragment length polymorphism methods. Results. Patients had significantly decreased frequency of the ε2 allele compared to controls. Patients who carry at least one ε2 allele had a significantly higher level of serum apolipoprotein E and significantly lower low density lipoprotein cholesterol levels compared to those who do not carry this allele. Conclusion. Our results suggest protective effect of apolipoprotein E ε2 allele on susceptibility for carotid plaque presence as well as low density lipoprotein cholesterol lowering effect in Serbian patients with carotid atherosclerosis. Further research of multiple gene and environmental factors that contribute to the appearance and the progression of atherosclerosis should be continued with respect to different populations.

References

Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973; 180(4093): 1332−9.

Herity NA, Ward MR, Lo S, Yeung AC. Review: Clinical aspects of vascular remodeling. J Cardiovasc Electrophysiol 1999; 10(7): 1016−24.

Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N, et al. Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 2002; 110(3): 331−40.

Ma Z, Choudhury A, Kang S, Monestier M, Cohen PL, Eisenberg RA. Accelerated atherosclerosis in ApoE deficient lupus mouse models. Clin Immunol 2008; 127(2): 168−75.

Matsuura E, Kobayashi K, Tabuchi M, Lopez LR. Oxidative mod-ification of low-density lipoprotein and immune regulation of atherosclerosis. Prog Lipid Res 2006; 45(6): 466−86.

Siest G, Pillot T, Régis-Bailly A, Leininger-Muller B, Steinmetz J, Galteau MM, et al Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem 1995; 41(8 Pt 1): 1068−86.

Voet D, Voet JG. Biochemistry. 2nd ed. New York, NY: John Wiley & Sons, Inc; 1995.

Weisgraber KH, Innerarity TL, Harder KJ, Mahley RW, Milne RW, Marcel YL, et al. The receptor-binding domain of human apo-lipoprotein E. Monoclonal antibody inhibition of binding. J Biol Chem 1983; 258(20): 12348−54.

Innerarity TL, Friedlander EJ, Rall SC, Weisgraber KH, Mahley RW. The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments. J Biol Chem 1983; 258(20): 12341−7.

Zannis VI, Breslow JL. Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by ge-netic variation and posttranslational modification. Biochemi-stry 1981; 20(4): 1033−41.

Ehnholm C, Lukka M, Kuusi T, Nikkila E, Utermann G. Apoli-poprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res 1986; 27(3): 227−35.

Xhignesse M, Lussier-Cacan S, Sing CF, Kessling AM, Davignon J. Influences of common variants of apolipoprotein E on meas-ures of lipid metabolism in a sample selected for health. Arte-rioscler Thromb 1991; 11(4): 1100−10.

Kamboh MI, Aston CE, Ferrell RE, Hamman RF. Impact of apo-lipoprotein E polymorphism in determining interindividual variation in total cholesterol and low density lipoprotein cho-lesterol in Hispanics and non-Hispanic whites. Atherosclerosis 1993; 98(2): 201−11.

Eichner JE, Dunn TS, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002; 155(6): 487−95.

Dallongeville J, Lussier-Cacan S, Davignon J. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis. J Lipid Res 1992; 33(4): 447−54.

Slooter AJ, Bots ML, Havekes LM, del Sol AI, Cruts M, Grobbee DE, et al. Apolipoprotein E and carotid artery atherosclerosis: The Rotterdam study. Stroke 2001; 32(9): 1947−52.

Karvonen J, Kauma H, Kervinen K, Ukkola O, Rantala M, Paivansalo M, et al. Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men. J Hypertens 2002; 20(12): 2371−8.

Djurić T, Stanković A, Končar I, Radak D, Davidović L, Alavantić D, et al. Association of MMP-8 promoter gene polymorphisms with carotid atherosclerosis: preliminary study. Atherosclerosis 2011; 219(2): 673−8.

Djurić T, Zivković M, Radak D, Jekić D, Radak S, Stojković L, et al. Association of MMP-3 5A/6A gene polymorphism with susceptibility to carotid atherosclerosis. Clin Biochem 2008; 41(16−17): 1326−9.

Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990; 31(3): 545−8.

Debette S, Lambert J, Gariépy J, Fievet N, Tzourio C, Dartigues J, et al. New insight into the association of apolipoprotein E genetic variants with carotid plaques and intima-media thickness. Stroke 2006; 37(12): 2917−23.

Pardo SCM, Janssens CAJW, Hofman A, Witteman JCM, Duijn CM. Apolipoprotein E gene is related to mortality only in normal weight individuals: the Rotterdam Study. Eur J Epidemiol 2008; 23(2): 135−42.

Beilby JP, Hunt CC, Palmer LJ, Chapman CM, Burley JP, McQuillan BM, et al. . Apolipoprotein E gene polymorphisms are asso-ciated with carotid plaque formation but not with intima-media wall thickening: results from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Stroke 2003; 34(4): 869−74.

Chutinet A, Suwanwela NC, Snabboon T, Chaisinanunkul N, Furie KL, Phanthumchinda K. Association between genetic polymor-phisms and sites of cervicocerebral artery atherosclerosis. J Stroke Cerebrovasc Dis 2012; 21(5): 379−85.

Andrade M, Thandi I, Brown S, Gotto A, Patsch W, Boerwinkle E. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet 1995; 56(6): 1379−90.

Smit M, Knijff P, Rosseneu M, Bury J, Klasen E, Frants R, et al. Apolipoprotein E polymorphism in The Netherlands and its effect on plasma lipid and apolipoprotein levels. Hum Genet 1988; 80(3): 287−92.

Stanković S, Glisic S, Alavanatić D. The effect of a gender differ-ence in the apolipoprotein E gene DNA polymorphism on serum lipid levels in a Serbian healthy population. Clin Chem Lab Med 2000; 38(6): 539−44.

Lenzen HJ, Assmann G, Buchwalsky R, Schulte H. Association of apolipoprotein E polymorphism, low-density lipoprotein cho-lesterol, and coronary artery disease. Clin Chem 1986; 32(5): 778−81.

Alvim RO, Freitas SRS, Ferreira NE, Santos PCJL, Cunha RS, Mill JG, et al. APOE polymorphism is associated with lipid profile, but not with arterial stiffness in the general population. Lipids Health Dis 2010; 9: 128.

Schaefer EJ, Lamon-Fava S, Johnson S, Ordovas JM, Schaefer MM, Castelli WP, et al. Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma li-poprotein levels. Results from the Framingham Offspring Study. Arterioscler Thromb 1994; 14(7):1105−13.

Wilson HM, Patel JC, Russell D, Skinner ER. Alterations in the concentration of an apolipoprotein E-containing subfraction of plasma high density lipoprotein in coronary heart disease. Clin Chim Acta 1993; 220(2): 175−87.

Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymor-phism and atherosclerosis. Arteriosclerosis 1988; 8(1): 1−21.