Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2016, vol. 25, nr 3, May-June, p. 471–478

doi: 10.17219/acem/38841

Publication type: original article

Language: English

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The APOE E4 Allele Confers Increased Risk of Ischemic Stroke Among Greek Carriers

Christopher Konialis1,A,B,C,D,E,F, Konstantinos Spengos2,B,C,E,F, Panagiotis Iliopoulos1,B,C, Sophia Karapanou1,B,C, Elias Gialafos2,B,E,F, Birgitta Hagnefelt1,B,C, Konstantinos Vemmos3,B,E,F, Nikolaos Zakopoulos3,B,E,F, Constantinos Pangalos1,A,E,F

1 InterGenetics, Diagnostic Genetics Center, Athens, Greece

2 1st Department of Neurology, Eginition Hospital, University of Athens School of Medicine, Athens, Greece

3 Department of Clinical Therapeutics, University of Athens, “Alexandra” University Hospital, Athens, Greece

Abstract

Background. Although several studies in various countries have indicated that the presence of the E4 allele of the apolipoprotein-E (APOE) gene is a risk factor for ischemic cerebrovascular disease, the strength of this association still remains a matter of debate.
Objectives. The aim of the study was to determine the frequency of the APOE E4 allele and various other gene polymorphisms in in a well-characterized sample of Greek patients and to evaluate the potential associations with the risk of ischemic stroke (IS) and coronary heart disease (CHD).
Material and Methods. A total of nine gene variants/polymorphisms – F5 (Leiden – R5 06Q, rs6025), F2 (20210G > A, rs1799963), F13A1 (V34L, rs5985), MTHFR (677C > T – A222V, rs1801133), MTHFR (1298A > C – E429A, rs1801131), FGB (–455G > A -c.-463G > A; rs1800790), SERPINE1 (PAI14G/5G – rs1799889), ACE (ACE I/D, rs1799752), ITGB3 (GPIIIa L33P, rs5918) and the APOE E2/E3/E4 alleles (rs7412, rs429358) – were genotyped in 200 newly diagnosed ischemic stroke (IS) patients, 165 patients with ischemic coronary heart disease (CHD) and 159 controls with no cerebroor cardiovascular disease (non-CVD). A statistical analysis was performed using univariate and multivariate logistic regression models.
Results. No significant association was found regarding most gene polymorphisms and the presence of IS or CHD in the patient cohort. However, the APOE E4 allele frequency was significantly higher (p = 0.02) among patients with ischemic stroke (IS) or IS + CHD (12.7%) when compared to the controls (5.1%). More accurately, E4 carriers had 2.66 and 2.71 times greater likelihood of IS or IS + CHD than non-carriers, respectively (OR = 2.66, 95% CI 1.39–5.07, OR = 2.71, 95% CI 0.98–7.48).
Conclusion. In contrast to some previous studies, these results support the role of the APOE E4 allele as an independent risk factor for ischemic stroke and ischemic coronary heart disease among Greek patients.

Key words

ischemic stroke, gene polymorphisms, apolipoprotein E gene, E4 allele

References (33)

  1. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y: American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2008 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, Circulation 2008, 117, e25
  2. Carandang R, Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Kannel WB, Wolf PA: Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. JAMA 2006, 296, 2939–2946.
  3. Liao D, Myers R, Hunt S, Shahar E, Paton C, Burke G, Province M, Heiss G: Familial history of stroke and stroke risk: The Family Heart Study. Stroke 1997, 28, 1908–1912.
  4. Schulz UG, Flossmann E and Rothwell PM: Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke 2004, 35, 819–824.
  5. Kastorini CM, Georgousopoulou E, Vemmos KN, Nikolaou V, Kantas D, Milionis HJ, Goudevenos JA, Panagiotakos DB: Comparative Analysis of Cardiovascular Disease Risk Factors Influencing Nonfatal Acute Coronary Syndrome and Ischemic Stroke. Am J Cardiol 2013, 112, 349–354.
  6. Bersano A, Ballabio E, Bresolin N, Candelise L: Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat 2008, 29, 776–795.
  7. Fan AZ, Fang J, Yesupriya A, Chang MH, Kilmer G, House M, Hayes D, Ned RM, Dowling NF, Mokdad AH: Gene polymorphisms in association with self-reported stroke in US adults. Appl Clin Genet 2010, 3, 23–28.
  8. Hamzi K, Tazzite A, Nadifi S: Large-scale meta-analysis of genetic studies in ischemic stroke: Five genes involving 152,797 individuals. Indian J Hum Genet. 2011, 17, 212–217.
  9. Ribalta J, Vallve JC, Girona J, Masana L: Apolipoprotein and apolipoprotein receptor genes, blood lipids and disease. Curr Opin Clin Nutr Metab Care 2003, 6, 177–187.
  10. Wilson PW, Schaefer EJ, Larson MG, Ordovas JM: Apolipoprotein E alleles and risk of coronary disease. A metaanalysis. Arterioscler Thromb Vasc Biol 1996, 16, 1250–1255.
  11. Tiret L, de Knijff P, Menzel HJ, Ehnholm C, Nicaud V, Havekes LM: ApoE polymorphism and predisposition to coronary heart disease in youths of different European populations. The EARS Study. European Atherosclerosis Research Study. Arterioscl Throm Vas 1994, 14, 1617–1624.
  12. Woo D, Kaushal R, Chakraborty R, Woo J, Haverbusch M, Sekar P, Kissela B, Pancioli A, Jauch E, Kleindorfer D, Flaherty M, Schneider A, Khatri P, Sauerbeck L, Khoury J, Deka R, Broderick J: Association of apolipoprotein E4 and haplotypes of the apolipoprotein E gene with lobar intracerebral hemorrhage. Stroke 2005, 36, 1874–1879.
  13. Souza DR, Campos BF, Arruda EF, Yamamoto LJ, Trindade DM, Tognola WA: Influence of the polymorphism of apolipoprotein E in cerebral vascular disease. Arq Neuropsiquiatr 2003, 61, 7–13.
  14. Biffi A, Sonni A, Anderson CD, Kissela B, Jagiella JM, Schmidt H, Jimenez-Conde J, Hansen BM, FernandezCadenas I, Cortellini L, Ayres A, Schwab K, Juchniewicz K, Urbanik A, Rost NS, Viswanathan A, Seifert-Held T, Stoegerer EM, Tomás M, Rabionet R, Estivill X, Brown DL, Silliman SL, Selim M, Worrall BB, Meschia JF, Montaner J, Lindgren A, Roquer J, Schmidt R, Greenberg SM, Slowik A, Broderick JP, Woo D, Rosand J: International Stroke Genetics Consortium:Variants at APOE influence risk of deep and
  15. Kuusisto J, Mykkänen L, Kervinen K, Kesäniemi YA, Laakso M: Apolipoprotein E4 phenotype is not an important risk factor for coronary heart disease or stroke in elderly subjects. Arterioscl Throm Vas 1995, 15, 1280–1286.
  16. Basun H, Corder EH, Guo Z, Lannfelt L, Corder LS, Manton KG, Winblad B, Viitanen M: Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. Stroke 1996, 1310–1315.
  17. MacLeod MJ, De Lange RP, Breen G, Meiklejohn D, Lemmon H, Clair DS: Lack of association between apolipoprotein E genotype and ischemic stroke in a Scottish population. Eur J Clin Invest 2001, 31, 570–573.
  18. Sudlow C, Martínez González NA, Kim J, Clark C: Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage?: Systematic review and meta-analyses of 31 studies among 5961 cases and 17 965 controls. Stroke 2006, 37, 364–370.
  19. Giassakis G, Veletza S, Papanas N, Heliopoulos I, Piperidou H: Apolipoprotein E and First-ever Ischaemic Stroke in Greek Hospitalized Patients. J Int Med Res 2007, 35, 127–133.
  20. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol (Adult Treatment Panel III). Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/ atp3_rpt.
  21. Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993, 24, 35–41.
  22. Milionis HJ, Gerotziafas G, Kostapanos MS, Vemmou A, Zis P, Spengos K, Elisaf M, Vemmos KN: Clopidogrel vs. aspirin treatment on admission improves 5-year survival after a first-ever acute ischemic stroke. Data from the Athens Stroke Outcome Project. Arch Med Res 2011, 42, 443–450.
  23. Ye Z, Liu EH, Higgins JP, Keavney BD, Lowe GD, Collins R, Danesh J: Seven haemostatic gene polymorphisms in coronary disease: Meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006, 367, 651–658.
  24. Antoniadi T, Hatzis T, Kroupis C, Economou-Petersen E, Petersen MB: Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in a Greek population of blood donors. Am J Hematol 1999, 61, 265–267.
  25. Koumas L, Costeas PA, Papaloizou A, Giantsiou-Kyriakou A: Genetic assessment of cardiovascular risk factors in the Greek Cypriot population. Thromb Res 2003, 112, 143–146.
  26. Gialeraki A, Politou M, Rallidis L, Merkouri E, Markatos C, Kremastinos D, Travlou A: Prevalence of prothrombotic polymorphisms in Greece. Genet Test 2008, 12, 541–547.
  27. Sklavounou E, Economou-Petersen E, Karadima G, Panas M, Avramopoulos D, Varsou A, Vassilopoulos D, Petersen MB: Apolipoprotein E polymorphism in the Greek population. Clin Genet 1997, 52, 216–218.
  28. Lanktree MB, Dichgans M, Hegele RA: Advances in genomic analysis of stroke: What have we learned and where are we headed? Stroke 2010, 41, 825–832.
  29. Cheng YC, Anderson CD, Bione S, Keene K, Maguire JM, Nalls M, Rasheed A, Zeginigg M, Attia J, Baker R, Barlera S, Biffi A, Bookman E, Brott TG, Brown RD Jr, Chen F, Chen WM, Ciusani E, Cole JW, Cortellini L, Danesh J, Doheny K, Ferrucci L, GraziaFranzosi M, Frossard P, Furie KL, Golledge J, Hankey GJ, Hernandez D, Holliday EG, Hsu FC, Jannes J, Kamal A, Khan MS, Kittner SJ, Koblar SA, Lewis M, Lincz L, Lisa A, Matarin M, Moscato P, Mychaleckyj JC, Parati EA, Parolo S, Pugh E, Rost NS, Schallert
  30. Lövkvist H, Sjögren M, Höglund P, Engström G, Jern C, Olsson S, Smith JG, Hedblad B, Andsberg G, Delavaran H, Jood K, Kristoffersson U, Norrving B, Melander O, Lindgren A: Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke? Eur J Neurol 2013, 20, 1284–1291.
  31. Mahley RW, Weisgraber KH, Huang Y: Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A 2006, 103, 5644–5651.
  32. Montagnana M, Danese E, Lippi G: Genetic risk factors of atherothrombosis. Pol Arch Med Wewn 2014, 124, 474–481.
  33. Lippi G and Mattiuzzi C: The biomarker paradigm: Between diagnostic efficiency and clinical efficacy. Pol Arch Med Wewn 2015, pii: AOP_15_026.
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