Molecular Biology Reports

, Volume 46, Issue 6, pp 6345–6351 | Cite as

Possible synergistic effect of apoE and LRP1 genotypes on metabolic syndrome development in Serbian patients

  • N. VučinićEmail author
  • K. Stankov
  • M. Đan
  • I. Barjaktarović
  • E. Stokić
  • L. J. Strajnić
  • D. Obreht
  • I. Đan
Original Article


The modern way of life contributes to the higher frequency of a complex state medically called metabolic syndrome (MetS), which is an inevitable consequence of several most common diseases of modern civilization. Patients with MetS have three times higher risk of experiencing a heart attack or a stroke and twice higher possibility to die from them. Serbia holds the infamous third place in Europe in mortality from heart disease, just behind Russia and Ukraine. The study explores the correlation of every combination of genotypes of apoE (apolipoprotein E) and LRP1 (low density receptor- related protein 1) genes with presence of MetS, and the connection with each anthropometric and biochemical parameter in both tested groups. Study demonstrates the impact of genotype combinations on the emergence and development of the MetS in Serbia. 63 patients and 30 controls were included in the study, aged from 19 to 65. Each person genotype was determined by the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) profile. Odds ratio (OR) values showed that the presence of apoE e3e4/LRP1 CC genotype combination of genotypes in patients multiplies the chance (7.6 times) for the occurrence of the MetS in comparison to the presence of other genotype combinations. Determining the genetic basis of MetS is one of the necessary steps in the prevention of disease, saving the cost of treatment, and in the design of targeted therapies.


Metabolic syndrome LRP1 gene variants apoE gene variants 



All the study participants made possible completion of this study. The study was supported by the Ministry of Education, Science and Technological Development, Republic of Serbia, Grant No. 179006.

Author contributions

Study conception and design: NV, ES, MD, KS. Data analysis and interpretation: NV. Drafting the article: ID, DO, IB. Critical revision of the article: ES, MD, IB, KS, LS, DO. Performed analysis on all samples, interpreted data, wrote manuscript, revised the article and acted as corresponding author: NV.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Ethical board of Clinical Center Vojvodina, Serbia and Ethical board of Medical Faculty Novi Sad, University of Novi Sad, Serbia approved this study. The study was performed according to the Declaration of Helsinki.

Informed consent

Signed informed consent was obtained from all individual participants included in the study.


  1. 1.
    Vučinić N, Djan I, Stokić E, Božin B, Obreht D, Stankov K et al (2014) Different associations of apoE gene polymorphism with metabolic syndrome in the Vojvodina Province (Serbia). Mol Biol Rep 41(8):5221–5227. CrossRefGoogle Scholar
  2. 2.
    Vučinić N, Stokić E, Đan I, Obreht D, Veličković N, Stankov K, Đan M (2017) The LRP1 gene polymorphism is associated with increased risk of metabolic syndrome prevalence in the Serbian population. BJMG 20(1):51–58. CrossRefGoogle Scholar
  3. 3.
    The European Group for the Study of Insulin Resistance (EGIR) (2002) The frequency of the WHO metabolic syndrome in European cohorts, and an alternative definition of the insulin resistance syndrome. Diabetes Metab. 28(5):364–376Google Scholar
  4. 4.
    Einhorn D, Reaven GM, Cobin RH et al (2003) American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 9:237–252Google Scholar
  5. 5.
    Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult treatment panel III) (2001) Executive summary of the third report of the national cholesterol education program (NCEP). JAMA 285(19):2486–2497Google Scholar
  6. 6.
    Micić D, Kendereški A, Šumarac-Dumanović M (1994) Insulinska rezistencija. Medicinska knjiga, Beograd, pp 89–97Google Scholar
  7. 7.
    Bruno G, Merletti F, Biggeri A, Bargero G, Ferrero S, Runzo C (2004) Metabolic syndrome as a predictor of all-cause and cardiovascular mortality in type 2 diabetes: the Casale Monferrato study. Diabetes Care 11:2689–2694CrossRefGoogle Scholar
  8. 8.
    Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J et al (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288(21):2709–2716CrossRefGoogle Scholar
  9. 9.
    Scuteri A, Najjar S, Morrell C, Lakatta E (2005) The metabolic syndrome in older individuals: prevalence and prediction of cardiovascular events. Diabetes Care 28:882–887CrossRefGoogle Scholar
  10. 10.
    Choi BC, Shi F (2001) Risk factors for diabetes mellitus by age, and sex: results of the National Population Health Survey. Diabetologia 44(10):1221–1231CrossRefGoogle Scholar
  11. 11.
    Serrano Ríos M, Caro JF, Carraro R, Gutiérrez- Fuentes JA (2005) Introduction. In: Serrano Ríos M, Caro JF, Carraro R, Gutiérrez- Fuentes JA (eds) The metabolic syndrome at the beginning of the XXI century: a genetic and molecular approach. Elsevier, Barcelona, pp 1–2Google Scholar
  12. 12.
    Ballantyne CM, Hoogeveen RC, McNeill AM, Heiss G, Schmidt MI, Duncan BB, Pankow JS (2008) Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study. Int J Obes 32:S21–S24. CrossRefGoogle Scholar
  13. 13.
    Blaha MJ, Bansal S, Rouf R, Golden SH, Blumenthal RS, Defilippis AP (2008) A practical “ABCDE” approach to the metabolic syndrome. Mayo Clin Proc 83:932–941CrossRefGoogle Scholar
  14. 14.
    Philips C, Lopez-Miranda H, Perez-Jimenez F, Mc Manus R, Roche H (2006) Genetic and nutrient determinants of the metabolic syndrome. Curr Opin Cardiol 21:185–193. CrossRefGoogle Scholar
  15. 15.
    VanWormer JJ, Boucher JL, Sidebottom AC, Sillah A, Knickelbine T (2017) Lifestyle changes and prevention of metabolic syndrome in the Heart of New Ulm Project. Prev Med Rep 6:242–245. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bouchareychas L, Raffai RL (2018) Apolipoprotein E and atherosclerosis: from lipoprotein metabolism to microRNA control of inflammation. J Cardiovasc Dev Dis 5(2):E30. CrossRefGoogle Scholar
  17. 17.
    Kypreos KE, Karagiannides I, Fotiadou EH, Karavia EA, Brinkmeier MS, Giakoumi SM, Tsompanidi EM (2009) Mechanisms of obesity and related pathologies: role of apolipoprotein E in the development of obesity. FEBS J 276:5720–5728. CrossRefGoogle Scholar
  18. 18.
    Hofmann SM, Zhou L, Perez-Tilve D, Greer T, Grant E, Wancata L et al (2007) Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. J Clin Investig 117:3271–3282. CrossRefGoogle Scholar
  19. 19.
    Anoop S, Anoop M, Meena K, Luthra K (2010) Apolipoprotein E polymorphism in cerebrovascular & coronary heart diseases. Indian J Med Res 132:363–378PubMedPubMedCentralGoogle Scholar
  20. 20.
    Herz J, Dk Strickland (2001) LRP: a multifunctional scavenger and signalling receptor. J Clin Investig 108(6):779–784. CrossRefGoogle Scholar
  21. 21.
    Jaeger S, Pietrzik CU (2008) Functional role of lipoprotein receptors in Alzheimer’s disease. Curr Alzheimer Res 5(1):15–25CrossRefGoogle Scholar
  22. 22.
    Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK (2008) LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev 88(3):887–918. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mao H, Lockyer P, Li L, Ballantyne CM, Patterson C, Xie Pi X (2017) Endothelial LRP1 regulates metabolic responses by acting as a co-activator of PPARγ. Nat Commun 8:14960. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kang DE, Saitoh T, Chen X, Xia Y, Masliah E, Hansen LA, Thomas RG, Thal LJ, Katzman R (1997) Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer’s disease. Neurology 49(1):56–61CrossRefGoogle Scholar
  25. 25.
    Kanekiyo T, Bu G (2014) The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease. Front Aging Neurosci 6:93. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Neels JG, Bovenschen N, van Zonneveld AJ, Lenting PJ (2000) Interaction between factor VIII and LDL receptor-related protein. Modulation of coagulation? Trends Cardiovasc Med 10(1):8–14CrossRefGoogle Scholar
  27. 27.
    Niemeier A, Kassem M, Toedter K, Wendt D, Ruether W, Beisiegel U et al (2005) Expression of LRP1 by human osteoblasts: a mechanism for the delivery of lipoproteins and vitamin K1 to bone. J Bone Miner Res 20:283–293. CrossRefGoogle Scholar
  28. 28.
    Meng H, Chen G, Zhang X, Wang Z, Thomas D, Giordano T et al (2011) Stromal LRP1 in lung adenocarcinoma predicts clinical outcome. Clin Cancer Res 17(8):2426–2433. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Vormittag R, Bencur P, Ay C, Tengler T, Vukovich T, Quehenberger P et al (2007) Low-density lipoprotein receptor-related protein 1 polymorphism 663 C>T affects clotting factor VIII activity and increases the risk of venous thromboembolism. J Thromb Haemost 5:497–502. CrossRefGoogle Scholar
  30. 30.
    IDF Consensus Group (2005) The IDF worldwide definition of the metabolic syndrome. In: 1st International congress on prediabetes and the metabolic syndrome. BerlinGoogle Scholar
  31. 31.
    Kassi E, Pervanidou P, Chrousos G (2011) Metabolic syndrome: definitions and controversies. BMC Med 9:48. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Friedewald WT, Lavy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of preparative ultracentrifuge. Clin Chem 18:499–502Google Scholar
  33. 33.
    Kocher TD, Thomas KW, Meyer A, Edwards SV, Paabo S, Villablanca FX, Wilson AC (1989) Dynamics of mitochondrial DNA evolution in animals: amplification and sequencing with conserved primers. Proc Natl Acad Sci USA 86:6196–6200CrossRefGoogle Scholar
  34. 34.
    Hixon JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleveage with HhaI. J Lipid Res 31(3):545–548Google Scholar
  35. 35.
    StatSoft, Inc. STATISTICA (data analysis software system) version 10. 2011, Accessed 27 Feb 2018
  36. 36.
    Beneš P, Jurajda M, Žaloudík J, Izakovičová-Hollá L, Vácha J (2003) C766T low-density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism and susceptibility to breast cancer. Breast Cancer Res 5:R77–R81. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Volcik KA, Barkley RA, Hutchinson RG, Mosley TH, Heiss G, Sharrett AR, Ballantyne CM, Boerwinkle E (2006) Apolipoprotein E polymorphisms predict low density lipoprotein cholesterol levels and carotid artery wall thicknes but not incident coronary heart disease in 12,491 ARIC study participants. Am J Epidemiol 164(4):342–348. CrossRefGoogle Scholar
  38. 38.
    Sima A, Lordan A, Stancu C (2007) Apolipoprotein E polymorphism-a risk factor for metabolic syndrome. Clin Chem Lab Med 45(9):1149–1153. CrossRefGoogle Scholar
  39. 39.
    Olivieri O, Martinelli N, Bassi A et al (2007) ApoE epsilon2/epsilon3/epsilon4 polymorphism, ApoC-III/ApoE ratio and metabolic syndrome. Clin Chem Lab Med 45:1149–1153. CrossRefGoogle Scholar
  40. 40.
    Scuteri A, Najjar SS, Muller D, Andres R, Morrell CH, Zonderman AB, Lakkata EG (2005) ApoE4 allele and the natural history of cardiovascular risk factors. Am J Physiol Endocrinol Metab 289:E322–E327. CrossRefGoogle Scholar
  41. 41.
    Hatanaka Y, Kamino K, Fukuo K, Mitsuda N, Nishiwaki-Ueda Y, Sato N et al (2000) Low density lipoprotein receptor-related protein gene polymorphisms and risk for late-onset Alzheimer’s disease in a Japanese population. Clin Genet 58(4):319–323CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, Faculty of MedicineUniversity of Novi SadNovi SadSerbia
  2. 2.Department of Biochemistry, Faculty of MedicineUniversity of Novi SadNovi SadSerbia
  3. 3.Healthcare ManagementClinical Center of VojvodinaNovi SadSerbia
  4. 4.Department of Biology and Ecology, Faculty of SciencesUniversity of Novi SadNovi SadSerbia
  5. 5.Department of General Education Subjects, Faculty of MedicineUniversity of Novi SadNovi SadSerbia
  6. 6.Center for Laboratory MedicineClinical Center of VojvodinaNovi SadSerbia
  7. 7.Department of Internal Medicine, Faculty of MedicineUniversity of Novi SadNovi SadSerbia
  8. 8.Department of Endocrinology, Diabetes and Metabolic DisordersClinical Center of VojvodinaNovi SadSerbia
  9. 9.Department of Dentistry, Faculty of MedicineUniversity of Novi SadNovi SadSerbia
  10. 10.Dentistry Clinic of VojvodinaNovi SadSerbia
  11. 11.Department of Forest and Conservation SciencesUniversity of British ColumbiaVancouverCanada
  12. 12.Department of Oncology, Faculty of MedicineUniversity of Novi SadNovi SadSerbia
  13. 13.Department of RadiotherapyInstitute of OncologySremska KamenicaSerbia

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